TWI828861B - 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives - Google Patents

Abstract

The present invention provides a novel compound or salt thereof that inhibits EGFR. According to one aspect of the present invention, there is provided a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

Description

7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives

The present invention relates to a replacement compound with epithelial growth factor receptor (Epidermal Growth Factor Receptor; EGFR) inhibitory effect and a pharmaceutical composition containing the compound as an active ingredient.

EGFR is a receptor-type tyrosine kinase that binds to epithelial growth factor (EGF) as a ligand in normal tissues to exert physiological functions. It contributes to proliferation or inhibits apoptosis in epithelial tissues ( Non-patent literature 1).

In addition, EGFR is also an oncogene and is known to be present in various cancer types, such as head and neck cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer, brain tumors, etc. Amplification of the EGFR gene or high expression or mutation of the protein (Non-Patent Document 2). In East Asian, European and American countries, approximately 90 to 105 people per 100,000 people die from cancer every year, accounting for the top cause of death (Non-Patent Document 3). Among them, the number of deaths caused by lung cancer reaches approximately 1.4 million people worldwide every year, and non-small cell lung cancer accounts for more than 80% of lung cancers. Therefore, it is expected to develop an effective treatment method (Non-patent Document 4).

In recent years, the causative genes of these cancers have been identified, and mutations in the EGFR gene are one of them, resulting in active mutant EGFR proteins. The active mutant EGFR protein is, for example, one in which part of penetrance factor 19 (amino acids 746-750, etc.) is deleted (EGFR (Del19)), or one in which the 858th amino acid mutates from leucine to arginine. (EGFR (L858R)), etc., in Japan, for example, this mutation has been reported in 20-40% of non-small cell lung cancer, and in Europe and the United States, this mutation has also been reported in 10-15% of non-small cell lung cancer. . Non-small cell lung cancer with these mutations is resistant to agents that inhibit the kinase activity of EGFR (EGFR inhibitors): gefitinib (trade name Iressa (registered trademark)) and erlotinib (trade name) Tarceva (registered trademark)) is highly sensitive, so these drugs are used as therapeutic drugs in Japan, Europe and the United States. However, if 6-12 months pass from the start of use, resistance to gefitinib and erlotinib is acquired and the therapeutic effect becomes weakened. Therefore, the acquired resistance is likely to occur in patients with highly sensitive variant EGFR. The treatment of small cell lung cancer has become a serious problem. It is known that about 50% of the acquired drug resistance is caused by the emergence of the second mutation in the EGFR gene, resulting in the drug-resistant variant EGFR protein (EGFR(Del19/ T790M) or EGFR (T790M/L858R)), and the development of therapeutic drugs that are also effective for non-small cell lung cancer with this drug-resistant mutant EGFR has become an important issue (Non-patent Document 5).

Later, EGFR inhibitors effective against drug-resistant mutant EGFR proteins (EGFR(Del19/T790M) or EGFR(T790M/L858R)) were developed, and osimertinib (trade name Tagrisso (registered trademark)) was approved in Japan or Europe and the United States. )). As a result, it was used clinically as a secondary therapeutic drug prescribed after gefitinib or erlotinib, which are primary therapeutic drugs for EGFR-positive lung cancer. However, it was found that if about 10 months pass after the use of osimertinib, the effect weakens again and drug resistance is acquired. Gene analysis was performed and the results showed that as an osimertinib-resistant mutation, the 797th amino acid changed from cysteine to serine or EGFR (Del19/T790M/C797S) or EGFR (T790M/ C797S/L858R). Therefore, there is a need to develop a treatment method that is also effective for non-small cell lung cancer with triple EGFR mutations that produce active mutations and two drug-resistant mutations (Non-Patent Document 6).

Recently, osimertinib has been used in clinical treatment systems as a primary treatment in addition to its previous use as a secondary treatment for EGFR-positive non-small cell lung cancer. When this situation is reported, in addition to the active mutation, a double mutant EGFR (Del19/C797S) or EGFR (L858R/C797S) in which the 797th amino acid is mutated to serine is produced as a new drug resistance mutation. . Therefore, in order to exhibit an effect on EGFR-positive lung cancer cells that are resistant or unresponsive to osimertinib, it is necessary to develop an EGFR inhibitor that inhibits this double mutant drug-resistant EGFR protein (Non-Patent Document 7). [Prior technical literature] [Patent Document]

[Patent Document 1] International Publication No. WO2013/118817 [Non-patent literature]

[Non-patent document 1] Nature Rev. Cancer, vol.6, pp803-811(2006) [Non-patent document 2] Current Opinion in Oncology, vol.13, pp506-513(2001) [Non-patent document 3] International Agency for Research on Cancer, WHO, Cancer Fact Sheets, "All Cancers" (2018) [Retrieved on February 13, 2019], Internet <URL: http://gco.iarc. fr/today/ data/factsheets/ cancers/ 39-All-cancers-fact-sheet.pdf＞ [Non-patent document 4] Lung Cancer, vol.69, pp1-12(2010) [Non-patent document 5] Nature Rev. Cancer, vol.10, pp760-774(2010) [Non-patent document 6] ESMO Open, vol.1, e000060(2016) [Non-patent document 7] J. Clin. Oncol., vol.36, pp841-849(2018)

[Problem to be solved by the invention]

Due to the situation of this treatment system, there is a need to develop a drug that is effective in both cases of drug-resistant mutation when osimertinib is used for secondary treatment and drug-resistant mutation when used in primary treatment. That is, by administering a drug whose inhibitory activity against wild-type EGFR is weak compared to the inhibitory activity against the following cells, it is expected that drug-resistant mutant EGFR can be inhibited at an dosage that does not cause severe side effects in the skin or digestive tract. The proliferation of non-small cell lung cancer cells. In addition to the active mutation, the 790th amino acid mutation of this cell line is methionine and the 797th amino acid mutation is serine. It shows erlotinib, Gemfil Cells with EGFR mutations that are resistant to osimertinib or osimertinib; or cells with the 797th amino acid changed to serine in addition to the active mutation and expressing EGFR that is resistant to osimertinib.

As described above, the current situation is that EGFR inhibitors are expected to be effective in cancer treatment, but their clinical effects are insufficient in cancers that develop active mutations and osimertinib-resistant mutations.

Due to the above-mentioned situation, novel compounds or salts thereof that inhibit EGFR are sought. Furthermore, it is also attempted to inhibit variant EGFR, such as EGFR (Del19/C797S), EGFR (L858R/C797S), EGFR (Del19/T790M/C797S) or EGFR (L858R/T790M/C797S). However, for wild-type EGFR (WT) Novel compounds or salts thereof with weak inhibitory activity. [Technical means to solve problems]

As a result of diligent research, the present inventors discovered a novel pyrimidine compound (7H-pyrrolo[2,3-d]pyrimidin-4-amine derivative) represented by the following formula (I). These compounds are novel compounds characterized by a structure in which pyrrolo[2,3-d]pyrimidine is used as the basic skeleton, the 5-position is substituted with a quinoline ring, and the 7-position is substituted with a bicyclic ring.

That is, one aspect of the present invention provides the following [1] to [16]. [1] A compound or a pharmaceutically acceptable salt thereof represented by the following general formula (I): [Chemical 1] [In the formula, R ¹ is a hydrogen atom or a C1-C3 alkyl group which may have a substituent, X is NR ² R ³ , OR ⁴ or a monocyclic or polycyclic saturated or unsaturated heterocyclic ring which may have a substituent group, R ² is a hydrogen atom, or a C1-C6 alkyl group which may have a substituent, R ³ is a hydrogen atom, C(=O)R ⁵ , C(=S)R ⁶ , S(=O) ₂ R ⁷ , C1-C6 alkyl group which may have a substituent, or C3-C7 cycloalkyl group which may have a substituent, R ⁴ is a hydrogen atom, C1-C6 alkyl group which may have a substituent, C3-C7 which may have a substituent Cycloalkyl, optionally substituted carbonylamine group, R ⁵ is an optionally substituted C1-C6 alkyl group, optionally substituted C3-C7 cycloalkyl group, optionally substituted C1-C6 alkoxy group , optionally substituted amino group, optionally substituted 4-10-membered monocyclic or polycyclic saturated heterocyclic group, optionally substituted 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group Heterocyclic group, a 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group that may have a substituent, R ⁶ is a hydrogen atom, a C1-C6 alkyl group that may have a substituent, or a C1-C6 group that may have a substituent Mono- or dialkylamino groups, C3-C7 cycloalkyl groups which may have substituents, or 4-10 members which may have substituents and have 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. For a monocyclic or polycyclic saturated heterocyclic group, R ⁷ is a C1-C6 alkyl group that may have a substituent, a C3-C7 cycloalkyl group that may have a substituent, or a saturated 5-10-membered group that may have a substituent. Or unsaturated heterocyclic group, 6-10 membered aromatic hydrocarbon group which may have substituents, Ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, n represents any integer from 0 to 3 ]. [2] The compound described in [1] or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or a C1-C3 alkyl group. [3] ^The compound as described in [ ¹ ] or [ ² ] or a pharmaceutically acceptable salt thereof, wherein A monocyclic saturated or unsaturated heterocyclic group with 5 to 7 members of heteroatoms in the atom, R ² is a hydrogen atom or a C1-C6 alkyl group, R ³ is C(=O)R ⁵ , C(=S) R ⁶ or C1-C6 alkyl (can have a cyano group, a halogen atom, or a 5-7 membered monocyclic unsaturated heterocyclic ring with 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms group as a substituent), R ⁴ is a hydrogen atom, R ⁵ is a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 mono or dialkylamino group which may have a substituent, or a 5 which may have a substituent. -10-membered monocyclic or polycyclic unsaturated heterocyclic group, or 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group, ^R6 is a C1-C6 mono- or dialkylamino group, or can be A monocyclic or polycyclic saturated heterocyclic group having a C1-C6 alkyl group and 4 to 10 members of 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. [4] The compound as described in any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. [5] The compound as described in any one of [1] to [4], or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom. [6] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to [5], wherein X is NR ² R ³ or has 1 to 3 atoms selected from nitrogen atoms, oxygen atoms, and A monocyclic saturated or unsaturated heterocyclic group with 5 to 7 members of the heteroatom in the sulfur atom, R ² is a hydrogen atom, R ³ is C(=O)R ⁵ , R ⁵ is C1- which may have a substituent C6 alkyl, C1-C6 alkoxy, C1-C6 mono- or dialkylamino, 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group that may have substituents, or 6-10-membered A monocyclic or polycyclic aromatic hydrocarbon group. [7] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to [6], wherein X is NR ² R ³ or has 1 to 3 atoms selected from nitrogen atoms, oxygen atoms, and A monocyclic saturated heterocyclic group with 5 to 7 members of the heteroatom in the sulfur atom, R ² is a hydrogen atom, R ³ is C(=O)R ⁵ , and R ⁵ is a C1-C6 alkyl group that may have a halogen atom , or a monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic ring with 5 to 10 members having a C1-C6 alkyl group and 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. base. [8] The compound as described in any one of [1] to [7] or a pharmaceutically acceptable salt thereof, wherein ring A is bicyclo[2.2.1]heptane. [9] The compound described in any one of [1] to [8] or a pharmaceutically acceptable salt thereof, wherein n is 0. [10] The compound as described in any one of [1] to [9] or a pharmaceutically acceptable salt thereof, wherein the above substituent is selected from the group consisting of halogen atom, cyano group, nitro group, amino group, hydroxyl group, and alkyl group , haloalkyl, cycloalkyl, aralkyl, alkoxy, methanesulfonyl, alkoxyalkyl, fluoromethoxy, mono or dialkylamino, carbonylamine, pendant oxy, carboxyl , alkoxycarbonyl group, saturated or unsaturated heterocyclic group and aromatic hydrocarbon group. [10-1] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to [9], wherein the above-mentioned substituent is selected from the group consisting of halogen atom, cyano group, nitro group, amine group, hydroxyl group, Alkyl, haloalkyl, cycloalkyl, aralkyl, alkoxy, methanesulfonyl, alkoxyalkyl, hydroxyalkyl, fluoromethoxy, mono or dialkylamino, mono or di Alkylaminoalkyl group, carbonylamino group, side oxy group, oxygen group, carboxyl group, alkoxycarbonyl group, phosphine oxide group, saturated or unsaturated heterocyclic group, heterocycloalkyl group and aromatic hydrocarbon group. [11] A compound or a pharmaceutically acceptable salt thereof, which is selected from the following compound group: (1) 6-ethynyl-7-(4-𠰌linyl bicyclo[2.2.1]heptan-1-yl )-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(2)N-(4-(4-amino-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-1H-pyrazole- 5-Formamide(3)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7- base)bicyclo[2.2.1]heptan-1-yl)-2,2-difluoroacetamide(4)N-(4-(4-amino-6-ethynyl-5-(quinoline- 3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methyl-1,2,4-ethadiazole -3-Formamide(5)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7 -Bicyclo[2.2.1]heptan-1-yl)-5-methylpyridine-2-carboxamide (6)N-(4-(4-amino-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)ethazole-2-methamide (7) N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1] Heptan-1-yl)pyridine-2-methamide(8)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)pyridin-3-methamide. [11-1] A compound or a pharmaceutically acceptable salt thereof, which is selected from the following compound group: (1) 6-ethynyl-7-(4-𠰌linylbicyclo[2.2.1]heptane-1 -yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(2)N-(4-(4-amino-6-ethynyl- 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-1H-pyra Azole-5-carboxamide(3)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)bicyclo[2.2.1]heptan-1-yl)-2,2-difluoroacetamide(4)N-(4-(4-amino-6-ethynyl-5-(quinoline) Phin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methyl-1,2,4-㗁Diazole-3-carboxamide(5)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine -7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyridine-2-methamide(6)N-(4-(4-amino-6-ethynyl- 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)ethazole-2-methamide ( 7)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2. 1]Heptan-1-yl)pyridin-2-methamide(8)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrole) And[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)pyridin-3-methamide(9)N-(4-(4-amino-6) -Ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrimidine-5-methyl Amide(10)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo [2.2.1]Heptan-1-yl)-1-cyclopropyl-1H-pyrazole-5-carboxamide (11)N-(4-(4-amino-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)isoethazole-5-methamide. [12] An antitumor agent containing the compound described in any one of [1] to [11-1] or a pharmaceutically acceptable salt thereof as an active ingredient. [13] A pharmaceutical composition containing the compound described in any one of [1] to [11-1] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [14] A method of treating tumors, characterized by administering the compound described in any one of [1] to [11-1] or a pharmaceutically acceptable salt thereof. [14-1] A method of treating tumors, characterized by administering an effective amount of the compound described in any one of [1] to [11-1] or a pharmaceutically acceptable salt thereof to the extent necessary. object. [15] The compound described in any one of [1] to [11-1] or a pharmaceutically acceptable salt thereof is used to treat tumors. [16] The use of a compound as described in any one of [1] to [11-1] or a pharmaceutically acceptable salt thereof, for producing an anti-tumor agent. [Effects of the invention]

According to one aspect of the present invention, there is provided a novel compound represented by the above general formula (I) that inhibits EGFR or a salt thereof.

The following formula (I): [Chemical formula 2] [In the formula, R ¹ is a hydrogen atom or a C1-C3 alkyl group that may have a substituent, X is NR ² R ³ , OR ⁴ , or a monocyclic or polycyclic saturated or unsaturated heterocyclic group that may have a substituent Ring group, R ² is a hydrogen atom, or a C1-C6 alkyl group which may have a substituent, R ³ is a hydrogen atom, C(=O)R ⁵ , C(=S)R ⁶ , S(=O) ₂ R ^7. A C1-C6 alkyl group which may have a substituent, or a C3-C7 cycloalkyl group which may have a substituent, R ⁴ is a hydrogen atom, a C1-C6 alkyl group which may have a substituent, or a C3- which may have a substituent. C7 cycloalkyl, optionally substituted carbonylamine group, R ⁵ is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C1-C6 alkoxy group, an amino group that may have a substituent, a 4-10-membered monocyclic or polycyclic saturated heterocyclic group that may have a substituent, a 5-10-membered monocyclic or polycyclic saturated heterocyclic group that may have a substituent. Saturated heterocyclic group, 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group which may have substituents, R ⁶ is a hydrogen atom, C1-C6 alkyl group which may have substituents, C1- which may have substituents C6 mono- or dialkylamino group, C3-C7 cycloalkyl group which may have a substituent, or 4-10 heteroatoms which may have a substituent and have 1 to 4 selected from nitrogen atoms, oxygen atoms and sulfur atoms. A membered monocyclic or polycyclic saturated heterocyclic group, R ⁷ is a C1-C6 alkyl group that may have a substituent, a C3-C7 cycloalkyl group that may have a substituent, or a 5-10 membered group that may have a substituent. Saturated or unsaturated heterocyclic group, 6-10 membered aromatic hydrocarbon group which may have substituents, Ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, n represents any one from 0 to 3 Integer] The compound of the present invention represented is a compound with pyrro[2,3-d]pyrimidine as the basic skeleton, and is a novel compound.

[Definition of substituent] In this specification, as a "substituent", unless otherwise indicated, examples include: hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, alkyl group, haloalkyl group, cycloalkyl group group, aralkyl group, alkoxy group, methanesulfonyl group, alkoxyalkyl group, fluoromethoxy group, mono or dialkylamino group, carbonylamino group, pendant oxygen group, carboxyl group, alkoxycarbonyl group, saturated or unsaturated heterocyclic groups, aromatic hydrocarbon groups, etc., when the above substituents are present, and when this is not indicated otherwise, the number is typically 1, 2 or 3, preferably 1 Or 2, preferably 1.

In one aspect of the invention, the substituent may be selected from the group consisting of halogen atoms, cyano groups, nitro groups, amine groups, hydroxyl groups, alkyl groups, haloalkyl groups, cycloalkyl groups, aralkyl groups, alkoxy groups, and methanesulfonyl groups. group, alkoxyalkyl, hydroxyalkyl, fluoromethoxy, mono or dialkylamino, mono or dialkylaminoalkyl, carbonylamino, pendant oxy, oxy, carboxyl, alkoxy Carbonyl group, phosphine oxide group, saturated or unsaturated heterocyclic group, heterocycloalkyl group and aromatic hydrocarbon group.

In this specification, the "halogen atom" specifically includes a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom, and a chlorine atom and a fluorine atom are preferred.

In this specification, "alkyl" represents a linear or branched saturated hydrocarbon group. Specifically, examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. Dibutyl, third butyl, pentyl, hexyl, etc.

In this specification, "haloalkyl" means a group in which one to all hydrogen atoms of a linear or branched saturated hydrocarbon group are substituted by the above-mentioned halogen atoms. Specifically, examples include: monofluoromethyl, difluoromethyl base, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 2,2, 2-Trifluoroethyl, etc.

In this specification, "aralkyl" means a group in which one hydrogen atom of an alkyl group is substituted by an aryl group. Specific examples include benzyl (phenylmethyl), phenyl ethyl (phenyl ethyl), and naphthyl. Methyl and naphthylethyl, etc.

In this specification, "alkoxy" means an oxy group having the above-mentioned alkyl group. Specific examples include: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, etc. .

In this specification, "cycloalkyl" represents a monocyclic or polycyclic saturated hydrocarbon group. Specific examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

In this specification, "mono-C1-C6 alkylamino group" means an amine group substituted with a linear or branched hydrocarbon group having 1 to 6 carbon atoms in place of one hydrogen atom. Specific examples include: methyl group Amino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, 2nd butylamino group, 3rd butylamino group, pentylamino group , hexylamine, etc.

In this specification, "di-C1-C6 alkylamino" means an amino group substituted with a linear or branched hydrocarbon group having 1 to 6 carbon atoms in place of two hydrogen atoms. Specifically, dimethyl methylamine group, diethylamino group, ethylmethylamino group, etc.

In this specification, "mono- or dialkylaminoalkyl group" means the above-mentioned alkyl group having at least one mono- or dialkylamino group. Examples include: methylaminomethyl, methylamino group Ethyl, ethylaminomethyl, ethylaminopropyl, dimethylaminomethyl and other mono or di-C1-C6 alkylamino-C1-C6 alkyl groups.

In this specification, "alkoxyalkyl" means the above-mentioned alkyl group having at least one of the above-mentioned alkoxy groups, and examples include: methoxymethyl, ethoxyethyl, methoxyethyl ( For example, 2-methoxyethyl), methoxypropyl and other C1-C6 alkoxy-C1-C6 alkyl groups.

In this specification, the "phosphine oxide group" means a phosphonyl group having at least one of the above-mentioned oxygen groups (for example, -P(=O)R ₂ (R is a halogen atom, an alkyl group or an aryl group)) group), examples include: methylphosphine oxide group, dimethylphosphine oxide group, and diphenylphosphine oxide group.

In this specification, "saturated heterocyclyl" means a monocyclic ring having at least 1 (preferably 1 to 5, more preferably 1 to 3) hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. Formula or polycyclic fully saturated heterocyclic groups, specifically, can include: azetidinyl, pyrrolidinyl, piperidinyl, piperidyl, hexamethyleneimino, pyridinyl, thio 𠰌linyl, homopiperyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,6-diazaspiro[3.3]heptane, etc.

In this specification, "unsaturated heterocyclic group" means a single heteroatom having at least 1 (preferably 1 to 5, more preferably 1 to 3) selected from a nitrogen atom, an oxygen atom, and a sulfur atom. A cyclic or polycyclic completely unsaturated or partially saturated heterocyclic group. Specifically, the completely unsaturated unsaturated heterocyclic group may include: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, furyl, ethazolyl, isothiazolyl (or isooxazolyl), oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridyl, pyrimidinyl 𠯤yl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, pyrrolopyridyl, imidazopyridyl, imidazopyridyl, pyridyl Azolopyridinyl, triazolopyridinyl, pyrrolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, benzofuranyl, benzothiazolyl, benzothienyl, benzothiazolyl, benzo Furyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quintilyl group, etc., as the partially saturated unsaturated heterocyclic group, include: indolinyl group, methylenedioxyphenyl group, Ethylenedioxyphenyl, dihydrobenzofuranyl, etc.

In this specification, "aromatic hydrocarbon group" means a cyclic substituent having an unsaturated bond, including carbon and hydrogen, and the cyclic π electron system includes 4e+2 (e is an integer above 1) electrons. Specifically, it can Examples: phenyl, naphthyl, tetrahydronaphthyl, etc.

In this specification, "heterocycloalkyl" means the above-mentioned alkyl group having the above-mentioned saturated or unsaturated heterocyclic ring, and specific examples include: pyridylmethyl, pyrrolidinylmethyl, pyridylmethyl, and the like.

In this specification, "bicyclic ring" means a polycyclic (such as 2-ring, 3-ring) saturated hydrocarbon ring with at least 2 (for example, 2 or 3) saturated hydrocarbon rings and adjacent rings each sharing at least 2 carbon atoms. Hydrocarbons, specifically, include: bicyclo[3.2.1]octane, bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, bicyclo[2.1.1 ] hexane, bicyclo[1.1.1]heptane, etc. Preferred examples include: bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, etc.

In this specification, "spiro ring" refers to a bicyclic organic compound having a ring bonded to only one atom. Examples include: spiro[4.5]decane, 6-oxa-3-azabicyclo[3.2.1 ]Heptane et al.

In the compound represented by the general formula (I) of the present invention, R ¹ is "a hydrogen atom or a C1-C3 alkyl group".

As the "C1-C3 alkyl group" represented by R ¹ , a methyl group, an ethyl group, an n-propyl group, and an isopropyl group are preferable, and a methyl group is more preferable. R ¹ is preferably a hydrogen atom or a methyl group, most preferably a hydrogen atom.

In the description of the group in this specification, "CA-CB" represents a group having carbon atoms of A to B. For example, "C1-C6 alkyl" represents an alkyl group having 1 to 6 carbon atoms, and "C6-C10 aromatic hydrocarbon group" represents a group in which an aromatic hydrocarbon group having 6 to 10 carbon atoms is bonded. Furthermore, "members A to B" means that the number of atoms (number of ring members) constituting the ring is A to B. For example, "4-10 membered saturated heterocyclic group" means a saturated heterocyclic group with 4-10 ring members.

In the compound represented by the general formula (I) of the present invention, ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, preferably bicyclo[2.2.1]heptane.

In the compound represented by the general formula (I) of the present invention, the bonding form of ring A is not limited. In the case of bicyclo[2.2.1]heptane, for example, the following patterns are included. Preferable is (1). [Chemical 3] In the case of bicyclo[2.2.2]octane, for example, the following patterns are included. Preferably (9). [Chemical 4]

In the compound represented by the general formula (I) of the present invention, X is NR ² R ³ , OR ⁴ , or a monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have a substituent.

As the "monocyclic or polycyclic saturated or unsaturated heterocyclic group" among the "monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have a substituent" represented by A monocyclic saturated or unsaturated heterocyclic group with 1 to 3 members selected from nitrogen atoms, oxygen atoms and heteroatoms in sulfur atoms and 5 to 7 members, more preferably pyridyl, pyrimidinyl, piperazyl, piperazyl, 𠯤yl, 𠰌linyl, azetidinyl, pyrrolidinyl, piperayl, 6-oxa-3-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[ 3.2.1] Heptane, more preferably 𠰌linyl group, piperayl group, more preferably 𠰌linyl group.

The "substituent" in the "monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have a substituent" represented by C6 alkyl group, more preferably side oxy group or methyl group.

The "monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have a substituent" represented by X preferably has 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. The 5-7-membered monocyclic saturated or unsaturated heterocyclic group is pyridyl, pyrimidinyl, pyridinyl, piperazyl, 1-methyl-2-oxopiperphenyl, pyridinyl, nitrogen Heterocyclobutyl, pyrrolidinyl, piperazyl, 6-oxa-3-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.2.1]heptane, or The piperazyl substituent represented by the following formula [Chemical 5] , more preferably, it is a piperonyl group, a piperonyl group, or a piperonyl group represented by the above formula, and more preferably, it is a piperonyl group.

^{Preferably , _} Preferably it is NR ² R ³ , or a 5- to 7-membered monocyclic saturated or unsaturated heterocyclic group with 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, more preferably NR ² R ^3. Or a monocyclic saturated heterocyclic group with 5 to 7 members having 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, more preferably NR ² R ³ .

In the compound represented by the general formula (I) of the present invention, R ² is a hydrogen atom or a C1-C6 alkyl group which may have a substituent.

The "C1-C6 alkyl group" in the "C1-C6 alkyl group which may have a substituent" represented by R ² is preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, and more preferably a methyl group .

The "substituent" in the "C1-C6 alkyl group which may have a substituent" represented by R ² is preferably the above-mentioned substituent, and more preferably is a halogen atom.

The "C1-C6 alkyl group which may have a substituent" represented by R ² is preferably a C1-C6 alkyl group, more preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and most preferably a methyl group .

R ² is preferably a hydrogen atom or a C1-C6 alkyl group, more preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.

In the compound represented by the general formula (I) of the present invention, R ³ is a hydrogen atom, C(=O)R ⁵ , C(=S)R ⁶ , S(=O) ₂ R ⁷ , and may have a substituent. C1-C6 alkyl, or C3-C7 cycloalkyl which may have substituents.

The "C1-C6 alkyl group" in the "C1-C6 alkyl group which may have a substituent" represented by R ³ is preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, and more preferably a methyl group .

The "substituent" in the "C1-C6 alkyl group which may have a substituent" represented by R ³ is preferably the above-mentioned substituent, more preferably a halogen atom, a cyano group, or 1 to 3 nitrogen atoms selected from A monocyclic unsaturated heterocyclic group with 5 to 7 members among heteroatoms in atoms, oxygen atoms and sulfur atoms, more preferably a cyano group, or 1 to 3 members selected from nitrogen atoms, oxygen atoms and sulfur atoms. The heteroatom is a monocyclic unsaturated heterocyclic group with 5 to 7 members, preferably a cyano group or a pyridyl group.

The "C1-C6 alkyl group which may have a substituent" represented by R ³ is preferably a C1-C6 alkyl group which may have a cyano group, or 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The 7-membered monocyclic unsaturated heterocyclic group as the C1-C6 alkyl group of the substituent is more preferably methyl, cyanomethyl or pyridylmethyl.

The "C3-C7 cycloalkyl group which may have a substituent" represented by R ³ is preferably a C3-C5 cycloalkyl group, more preferably a cyclopropyl group or a cyclobutyl group.

R ³ is preferably C(=O)R ⁵ , C(=S)R ⁶ , or a C1-C6 alkyl group which may have a substituent, more preferably C(=O)R ⁵ , C(=S)R ^6. C1-C6 alkane that may have a cyano group, or a 5- to 7-membered monocyclic unsaturated heterocyclic group selected from 1 to 3 heteroatoms among nitrogen atoms, oxygen atoms, and sulfur atoms as substituents. The base is more preferably C(=O)R ⁵ or C(=S)R ⁶ , and the most preferred is C(=O)R ⁵ .

In the compound represented by the general formula (I) of the present invention, R ⁴ is a hydrogen atom, a C1-C6 alkyl group which may have a substituent, a C3-C7 cycloalkyl group which may have a substituent, or a carbonyl group which may have a substituent. Amino group.

As the "C1-C6 alkyl group which may have a substituent" represented by R ⁴ , a C1-C6 alkyl group is preferred, and a methyl group is more preferred.

The "C3-C7 cycloalkyl group which may have a substituent" represented by R ⁴ is preferably a C3-C7 cycloalkyl group, more preferably a cyclopropyl group or a cyclobutyl group.

The "carbonylamino group which may have a substituent" represented by R ⁴ is preferably a carbonylamino group which may have a C1-C6 alkyl group, and more preferably a methylcarbonylamino group or a dimethylcarbonylamino group.

R ⁴ is preferably a hydrogen atom or a C1-C6 alkyl group, more preferably a hydrogen atom.

In the compound represented by the general formula (I) of the present invention, R ⁵ is a C1-C6 alkyl group which may have a substituent, a C3-C7 cycloalkyl group which may have a substituent, or a C1-C6 alkyl group which may have a substituent. Oxygen group, amino group which may have a substituent, a 4-10-membered monocyclic or polycyclic saturated heterocyclic group which may have a substituent, a 5-10-membered monocyclic or polycyclic saturated heterocyclic group which may have a substituent Unsaturated heterocyclic group, a 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group which may have a substituent.

The "C1-C6 alkyl group" in the "C1-C6 alkyl group which may have a substituent" represented by R ⁵ is preferably a methyl group.

The "substituent" in the "C1-C6 alkyl group which may have a substituent" represented by R ⁵ is preferably the above-mentioned substituent, more preferably a halogen atom, a C1-C6 alkoxy group, a C1-C6 mono- or The dialkylamino group is preferably a fluorine atom, a methoxy group, an ethoxy group, a monomethylamino group, or a dimethylamino group, and the most preferably is a fluorine atom.

The "C1-C6 alkyl group which may have a substituent" represented by R ⁵ is preferably C1 which may have a halogen atom, a C1-C6 alkoxy group, or a C1-C6 mono- or dialkylamino group as a substituent. -C6 alkyl group, more preferably a C1-C6 alkyl group which may have a fluorine atom, a methoxy group, an ethoxy group, a monomethylamino group or a dimethylamino group as a substituent, more preferably a C1-C6 alkyl group which may have a fluorine atom C1-C6 alkyl, preferably difluoromethyl.

The "C3-C7 cycloalkyl group which may have a substituent" represented by R ⁵ is preferably a C3-C5 cycloalkyl group, more preferably a cyclopropyl group or a cyclobutyl group.

As the "C1-C6 alkoxy group which may have a substituent" represented by R ⁵ , a C1-C6 alkoxy group is preferred, and a methoxy group, an ethoxy group, or a pyridine-2-ylmethoxy group is more preferred. , more preferably ethoxy and pyridine-2-ylmethoxy.

The "optionally substituted amino group" represented by R ⁵ is preferably a C1-C6 monoalkylamino or dialkylamino group, more preferably a C1-C6 monoalkylamino group, and more preferably an ethylamino group.

The "4-10-membered monocyclic or polycyclic saturated heterocyclic group which may have a substituent" represented by R ⁵ preferably has 1 to 4 members selected from nitrogen atoms, oxygen atoms and sulfur atoms. The heteroatom is a monocyclic or polycyclic fully saturated heterocyclic group with 4 to 10 members, and is more preferably an azetidinyl, pyrrolidinyl, or 𠰌linyl group.

As "a 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group that may have a substituent" represented by R ⁵ , preferably a monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group with 5 to 10 members with 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, preferably ta 𠯤 base, pyrimidinyl, ethazolyl, thiadiazolyl, pyridyl, pyridyl, imidazolyl, furyl, isothiazolyl, triazolopyridyl, triazolyl, tris𠯤yl, thiazolyl, Thiadiazolyl, imidazopyrazolyl, pyrazolyl, more preferably isothiazolyl, pyrazolyl, thiadiazolyl, thiadiazolyl, pyrazolyl, pyrazolyl, more preferably pyrazolyl , ethazolyl, oxadiazolyl, pyridyl, pyridyl.

In one aspect of the present invention, the "5-10-membered monocyclic or polycyclic unsaturated heterocyclic group which may have a substituent" represented by R ⁵ is a "5-10-membered monocyclic or polycyclic unsaturated heterocyclic group" The cyclic unsaturated heterocyclyl group may be an imidazopyridyl group or an imidazopyridyl group.

The "substituent" of the "5-10-membered monocyclic or polycyclic unsaturated heterocyclic group which may have a substituent" represented by R ⁵ is preferably the above-mentioned substituent, more preferably a halogen atom, cyanide Group, side oxy group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 Mono- or dialkylamino group, C1-C6 alkylsulfonyl group, C3-C7 cycloalkyl group or C6-C10 aromatic hydrocarbon group, preferably fluorine atom, chlorine atom, cyano group, side oxygen group, C1-C6 Alkyl, monofluoromethyl, methoxyethyl, methoxy, monofluoromethoxy, dimethylamino, methanesulfonyl, cyclopropyl or phenyl, preferably C1-C6 alkyl , the best is methyl.

In one aspect of the present invention, the "substituent" of the "5-10-membered monocyclic or polycyclic unsaturated heterocyclic group that may have a substituent" represented by R ⁵ can be a hydroxyalkyl group, a monocyclic group, or a hydroxyalkyl group. Or dialkylaminoalkyl, phosphine oxide or 𠰌linylmethyl, preferably hydroxymethyl, methylaminomethyl, dimethylaminomethyl or 𠰌linylmethyl.

The "5-10-membered monocyclic or polycyclic unsaturated heterocyclic group that may have a substituent" represented by R ⁵ may have a halogen atom, a cyano group, a side oxy group, or a C1-C6 alkane. Base, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 mono or dialkylamino, C1- The group consisting of C6 alkylsulfonyl group, C3-C7 cycloalkyl group and C6-C10 aromatic hydrocarbon group serves as a substituent and has 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. 5 to 10-membered monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group, more preferably, it can have a halogen atom, a cyano group, a side oxygen group, a C1-C6 alkyl group, a C1-C6 halogen Alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 mono or dialkylamino, C1-C6 alkylsulfonyl , the group consisting of C3-C7 cycloalkyl and C6-C10 aromatic hydrocarbon groups as substituents include pyridinyl, pyrimidinyl, ethazolyl, oxadiazolyl, pyridinyl, and imidazolyl. , furanyl, isothiazolyl, triazolopyridinyl, triazolyl, trioxyl, thiazolyl, thiadiazolyl, imidazopyridyl or pyrazolyl, preferably having C1-C6 alkyl The base is pyridyl, pyrimidinyl, ethazolyl, oxadiazolyl, pyridyl, pyridyl, imidazolyl, furanyl, isothiazolyl, triazolopyridyl, triazolyl, trioxadiazolyl, Thiazolyl, thiadiazolyl, imidazopyridyl or pyrazolyl, more preferably isothiazolyl, pyrazolyl, thiazolyl, thiadiazolyl or pyrazolyl which may have C1-C6 alkyl group , pyrazolyl, more preferably pyrazolyl, ethazolyl, oxadiazolyl, pyridyl, or pyrazolyl which may have a C1-C6 alkyl group.

In one aspect of the present invention, the "5-10-membered monocyclic or polycyclic unsaturated heterocyclic group that may have a substituent" represented by R ⁵ may have a group selected from the group consisting of a halogen atom and a cyano group. , side oxy group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 mono Or dialkylamino, C1-C6 alkylsulfonyl, C3-C7 cycloalkyl, hydroxyalkyl, mono or dialkylaminoalkyl, phosphine oxide, 𠰌linylmethyl and C6-C10 A 5- to 10-membered monocyclic or polycyclic completely unsaturated or Partially saturated heterocyclic group, more preferably, can have a group selected from halogen atom, cyano group, side oxygen group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group-C1-C6 alkyl group, C1 -C6 alkoxy, C1-C6 haloalkoxy, C1-C6 mono or dialkylamino, C1-C6 alkylsulfonyl, C3-C7 cycloalkyl, hydroxyalkyl, mono or dialkyl The groups in the group consisting of aminoalkyl group, phosphine oxide group, oxalyl methyl group and C6-C10 aromatic hydrocarbon group are pyridine group, pyrimidinyl group, oxazolyl group, oxadiazolyl group and pyridyl group as substituents. base, pyridyl, imidazolyl, furyl, isothiazolyl, triazolopyridyl, triazolyl, trioxyl, thiazolyl, thiadiazolyl, imidazopyridyl, imidazopyridyl, imidazole Pyridyl or pyrazolyl, more preferably pyridyl, pyrimidinyl, oxazolyl, oxadiazolyl, pyridyl, pyridyl, imidazolyl, furyl, isozoyl, which may have C1-C6 alkyl. Thiazolyl, triazolopyridinyl, triazolyl, trisulfazolyl, thiazolyl, thiadiazolyl, imidazopyridyl, imidazopyridyl, imidazopyridyl or pyrazolyl, more preferably It is an isothiazolyl group, a pyrazolyl group, an ethazolyl group, a sadiazolyl group, a pyrazolyl group, or a pyrazolyl group which may have a C1-C6 alkyl group, and more preferably a pyrazolyl group which may have a C1-C6 alkyl group. , ethazolyl, oxadiazolyl, pyridyl, pyridyl.

In one aspect of the present invention, the "5-10-membered monocyclic or polycyclic unsaturated heterocyclic group which may have a substituent" represented by R ⁵ includes, for example, the following structure. [Chemical 6]

As the "monocyclic or polycyclic aromatic hydrocarbon group of 6 to 10 members which may have a substituent" represented by R ⁵ , it is preferably a monocyclic or polycyclic aromatic hydrocarbon group of 6 to 10 members, more preferably is phenyl.

R ⁵ is preferably a C1-C6 alkyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, an amino group which may have a substituent, a 5-10 membered monocyclic ring which may have a substituent, or Polycyclic unsaturated heterocyclic group, or 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group which may have substituents, more preferably C1-C6 alkyl or C1-C6 alkoxy which may have substituents. group, C1-C6 mono- or dialkylamino group, 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group which may have substituents, or 6-10-membered monocyclic or polycyclic aromatic group Family hydrocarbon group, more preferably a C1-C6 alkyl group that may have a halogen atom, a C1-C6 alkoxy group, or a C1-C6 mono or dialkylamino group as a substituent; C1-C6 alkoxy group; C1-C6 mono group Or dialkylamino group; can have a group selected from halogen atom, cyano group, side oxygen group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group-C1-C6 alkyl group, C1-C6 Alkoxy group, C1-C6 haloalkoxy group, C1-C6 mono or dialkylamino group, C1-C6 alkylsulfonyl group, C3-C7 cycloalkyl group and C6-C10 aromatic hydrocarbon group A 5- to 10-membered monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group with 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms as a substituent; or 6 -10-membered aromatic hydrocarbon group, preferably a C1-C6 alkyl group that may have a halogen atom; it may have a C1-C6 alkyl group and 5 of 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms ~10-membered monocyclic or polycyclic completely unsaturated or partially saturated heterocyclic group.

In one aspect of the present invention, R ⁵ is a C1-C6 alkyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, an amine group which may have a substituent, or a 5-C6 alkyl group which may have a substituent. A 10-membered monocyclic or polycyclic unsaturated heterocyclic group, or a 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group that may have a substituent, more preferably a C1-C6 alkane that may have a substituent. group, C1-C6 alkoxy group, C1-C6 mono- or dialkylamino group, 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group that may have substituents, or 6-10-membered monocyclic group Cyclic or polycyclic aromatic hydrocarbon group, more preferably C1-C6 alkyl group which may have a halogen atom, C1-C6 alkoxy group, or C1-C6 mono- or dialkylamino group as a substituent; C1-C6 alkyl group Oxygen group; C1-C6 mono- or dialkylamino group; can have a group selected from halogen atom, cyano group, side oxygen group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group-C1- C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 mono or dialkylamino, C1-C6 mono or dialkylamino C1-C6 The group consisting of alkyl group, C1-C6 alkylsulfonyl group, C3-C7 cycloalkyl group, phosphine oxide group and C6-C10 aromatic hydrocarbon group serves as a substituent and has 1 to 4 atoms selected from nitrogen atoms, 5-10 membered monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group or heterocycloalkyl group of heteroatoms in oxygen atom and sulfur atom; or 6-10 membered aromatic hydrocarbon group, preferably It is a C1-C6 alkyl group that may have a halogen atom; it may have a C1-C6 alkyl group and has 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. It is a monocyclic or polycyclic ring with 5 to 10 members. The ring type is completely unsaturated or partially saturated heterocyclyl.

In the compound represented by the general formula (I) of the present invention, R ⁶ is a hydrogen atom, a C1-C6 alkyl group which may have a substituent, a C1-C6 mono- or dialkylamino group which may have a substituent, or a C1-C6 mono- or dialkylamino group which may have a substituent. A C3-C7 cycloalkyl group with a substituent, or a monocyclic or polycyclic saturated heterocyclic group with 4 to 10 members that may have a substituent and has 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. ring base.

As the "C1-C6 alkyl group which may have a substituent" represented by R ⁶ , a C1-C6 alkyl group is preferred, and an ethyl group is more preferred.

As the "C1-C6 mono- or dialkylamino group which may have a substituent" represented by R ⁶ , a C1-C6 mono- or dialkylamino group is preferred, and a C1-C6 monoalkylamino group is more preferred. More preferably, it is ethylamino group.

As the "C3-C7 cycloalkyl group which may have a substituent" represented by R ⁶ , a C3-C7 cycloalkyl group is preferable, a C3-C5 cycloalkyl group is more preferable, and a cyclopropyl group or a cyclobutyl group is more preferable. .

As R ⁶ represents "a monocyclic or polycyclic saturated heterocyclic group of 4 to 10 members which may have a substituent and has 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms""A 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group with 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms", preferably azetidinyl, pyrrolidine 1, 6-diazaspiro[3.3]heptane, more preferably 2,6 diazacyclo[3.3]heptane.

As R ⁶ represents "a monocyclic or polycyclic saturated heterocyclic group of 4 to 10 members which may have a substituent and has 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms" The "substituent" is preferably the above-mentioned substituent, more preferably a C1-C6 alkyl group, and more preferably a methyl group.

As R ⁶ represents "a monocyclic or polycyclic saturated heterocyclic group with 4 to 10 members which may have a substituent and has 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms", Preferably, it is a monocyclic or polycyclic saturated heterocyclic group with 4 to 10 members that can have a C1-C6 alkyl group and 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and more preferably It is 2-methyl-2,6diazacyclo[3.3]heptane.

R ⁶ is preferably a C1-C6 mono- or dialkylamino group which may have a substituent, or a C1-C6 mono- or dialkylamino group which may have a substituent and has 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. A monocyclic or polycyclic saturated heterocyclic group, preferably a C1-C6 mono- or dialkylamino group, or a C1-C6 alkyl group with 1 to 4 atoms selected from nitrogen atoms, oxygen atoms and The heteroatom in the sulfur atom is a monocyclic or polycyclic saturated heterocyclic group with 4 to 10 members, and is more preferably an ethylamino group or 2-methyl-2,6 diazacyclo[3.3]heptane.

In the compound represented by the general formula (I) of the present invention, R ⁷ is a C1-C6 alkyl group which may have a substituent, a C3-C7 cycloalkyl group which may have a substituent, or a 5-10 membered group which may have a substituent. A monocyclic or polycyclic saturated or unsaturated heterocyclic group, a 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group which may have a substituent.

As the "C1-C6 alkyl group which may have a substituent" represented by R ⁷ , a C1-C6 alkyl group is preferred, and a methyl or ethyl group is more preferred.

The "C3-C7 cycloalkyl group which may have a substituent" represented by R ⁷ is preferably a C3-C7 cycloalkyl group, more preferably a cyclopropyl group or a cyclobutyl group.

As the "C1-C6 haloalkyl group which may have a substituent" represented by R ⁷ , a C1-C6 haloalkyl group is preferred, and a trifluoroethyl group is more preferred.

The "5-10-membered monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have a substituent" represented by R ⁷ preferably has 1 to 4 members selected from nitrogen atoms, oxygen atoms and The heteroatom in the sulfur atom is a monocyclic or polycyclic saturated or unsaturated heterocyclic group with 5 to 10 members, more preferably a pyridyl group or a pyrimidinyl group.

As the "monocyclic or polycyclic aromatic hydrocarbon group of 6 to 10 members which may have a substituent" represented by R ⁷ , it is preferably a monocyclic or polycyclic aromatic hydrocarbon group of 6 to 10 members, more preferably is phenyl.

In the compound represented by the general formula (I) of the present invention, n is any integer from 0 to 3, preferably 0 or 1, and more preferably 0.

In a preferred aspect of the present invention, it is a compound or a pharmaceutically acceptable salt thereof, which is in the general formula (I), R ¹ is a hydrogen atom or a C1-C3 alkyl group, X is NR ² R ^3. OR ⁴ , or a monocyclic saturated or unsaturated heterocyclic group with 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms with 5 to 7 members, R ² is a hydrogen atom or C1- C6 alkyl group, R ³ is a hydrogen atom, C(=O)R ⁵ , C(=S)R ⁶ or C1-C6 alkyl group (can have a cyano group, or 1 to 3 atoms selected from nitrogen atoms, oxygen atoms and a 5- to 7-membered monocyclic unsaturated heterocyclic group as a substituent for the heteroatom in the sulfur atom), R ⁴ is a hydrogen atom, and R ⁵ is a C1-C6 alkyl group or C1-C6 alkyl group that may have a substituent. Oxygen group, C1-C6 mono- or dialkylamino group, 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group which may have substituents, or 6-10-membered monocyclic or polycyclic group Aromatic hydrocarbon group, R ⁶ is a C1-C6 mono or dialkylamino group, or may have a C1-C6 alkyl group and 1 to 4 4 to 10 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. It is a monocyclic or polycyclic saturated heterocyclyl group, ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, n is 0 or 1.

More preferably, it is the following compound or a pharmaceutically acceptable salt thereof, which is in the general formula (I) of the present invention, R ¹ is a hydrogen atom, X is NR ² R ³ , or has 1 to 3 nitrogen atoms selected from , a monocyclic saturated or unsaturated heterocyclic group with 5 to 7 members of heteroatoms in oxygen atoms and sulfur atoms, R ² is a hydrogen atom, R ³ is C(=O)R ⁵ , R ⁵ may be substituted A C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 mono- or dialkylamino group, a 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group that may have a substituent, or 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group, ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, n is 0 or 1.

More preferably, it is the following compound or a pharmaceutically acceptable salt thereof, which is in the general formula (I) of the present invention, R ¹ is a hydrogen atom, X is NR ² R ³ , or has 1 to 3 nitrogen atoms selected from , a monocyclic saturated heterocyclic group with 5 to 7 members of heteroatoms in oxygen atoms and sulfur atoms, R ² is a hydrogen atom, R ³ is C(=O)R ⁵ , R ⁵ is C1 which may have a halogen atom -C6 alkyl, a monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group that may have 5 to 10 members of C1-C6 alkyl, ring A is bicyclo[2.2.1]heptane, n is 0 .

Specific examples of the compounds of the present invention include compounds produced in the following examples, but are not limited thereto. One embodiment of the present invention is a compound selected from the following (1) to (8), or a pharmaceutically acceptable salt thereof. These compounds have particularly strong pharmacological activity, which can be seen in the persistence of high blood concentrations and good oral absorption. (1)6-Ethynyl-7-(4-𠰌linylbicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine (2)N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]Heptan-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (3)N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]Heptan-1-yl)-2,2-difluoroacetamide (4)N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]Heptan-1-yl)-5-methyl-1,2,4-oxadiazole-3-methamide (5)N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]Heptan-1-yl)-5-methylpyridine-2-methamide (6)N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]Heptan-1-yl)ethazole-2-methamide (7)N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]Heptan-1-yl)pyridin-2-methamide (8)N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]heptane-1-yl)d-3-methamide (9)N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]heptan-1-yl)pyrimidine-5-methamide (10)N-(4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]Heptan-1-yl)-1-cyclopropyl-1H-pyrazole-5-methamide (11)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]Heptan-1-yl)isoethazole-5-methamide

<Method for producing the compound represented by formula (I)> Next, the method for producing the compound of the present invention will be described. The compound represented by formula (I) of the present invention can be produced, for example, by the following production method or the method shown in the Examples. However, the method for producing the compound represented by formula (I) of the present invention is not limited to these reaction examples. The products obtained in each step can be isolated and purified using known separation and purification methods, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. or can be supplied to the next step without isolation and purification. steps. In addition, in the following production methods, regardless of whether it is described or not, a protective group can be introduced or removed as necessary, and the order of each step can be appropriately changed. [Manufacturing method 1] [Chemical 7] [In the formula, Y represents NH or O, P ₁ represents a hydrogen atom or a protecting group for an amine group, L ₁ , L ₂ , L ₃ and L ₄ represent leaving groups, and ring A and n are synonymous with the above]

(Step 1) This step is a method of producing a compound represented by general formula (IV) by reacting a compound represented by general formula (II) and a compound represented by general formula (III) in the presence of a base. The leaving group represented by L ₁ in the general formula (II) is a fluorine atom or a chlorine atom. In addition, the leaving group represented by L ₂ is an iodine atom or a bromine atom. The compounds represented by general formulas (II) and (III) can be commercially available or can be produced according to known methods. The compound represented by the general formula (III) can be used in an amount of 1 to 10 moles, preferably 1 to 3 moles, per 1 mole of the compound represented by the general formula (II). The base used in this step can be, for example, triethylamine, diisopropylethylamine, pyridine and other organic bases; or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium phosphate, etc. Potassium tributyrate and other inorganic bases. The usage amount of the base is usually 1 mole to excess mole, preferably 1 to 3 mole, based on 1 mole of the compound represented by the general formula (II). The reaction solvent is not particularly limited as long as it does not hinder the reaction, and suitable examples include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylstyrene, dimethylformamide, N-methylpyrrolidone, etc. or its mixed solvents, etc. The reaction temperature is usually 0°C to 200°C, preferably 50°C to 120°C. The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.

(Step 2) This step is a step for producing the compound represented by formula (VI) by the zodiac reaction of the compound represented by formula (IV) and the compound represented by formula (V). As a method for the Nagoya reaction, a generally known method (for example, a method described in Chemical Reviews, Vol. 107, p. 874 (2007)) can be used, or a method based on the method can be used. For example, it can be carried out using a transition metal catalyst and In the presence of a base, the reaction is carried out in a solvent that does not adversely affect the reaction. As the transition metal catalyst, for example, palladium catalysts (such as palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichloro[1,1 '-Bis(diphenylphosphine)ferrocene]palladium, tris(dibenzylideneacetone)dipalladium(0), etc.); copper catalyst (such as copper bromide, copper iodide, etc.), etc. The amount of the transition metal catalyst that can be used is suitably in the range of 0.001 to 1 mole per 1 mole of the compound represented by formula (IV). If necessary, as palladium ligands, triphenylphosphine, tris(2-furyl)phosphine, 1,1'-bis(diphenylphosphine)ferrocene, 4,5-bis(diphenyl)phosphine can be used Phosphine)-9,9'-dimethyl𠮿 , 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-di- tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, etc. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. Examples include: tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and N,N-dimethyl. Formamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, benzene, toluene, acetonitrile, dimethylsulfoxide, water, or mixed solvents thereof. In this step, as the base, organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine can be used; or sodium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate. , sodium hydroxide, sodium hydride, potassium phosphate, sodium phosphate, potassium tertbutyrate and other inorganic bases. The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours. The reaction temperature is usually 25°C to 200°C, preferably 30°C to 100°C.

(step 3) This step is a method of producing a compound represented by general formula (VII) by reacting it with a compound represented by general formula (VI) in the presence of a base. In this step, as the base, organic bases such as diisopropylethylamine, pyridine, and tetrabutylammonium fluoride can be used; or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. , potassium phosphate, sodium phosphate, potassium tertbutyrate and other inorganic bases. Examples of the reaction solvent that can be used include: tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethyl Acetamide, N-methyl-2-pyrrolidone, benzene, toluene, acetonitrile, dimethylstyrene, water, or mixed solvents thereof. The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours. The reaction temperature is usually 25°C to 200°C, preferably 50°C to 100°C.

(Step 4) This step is a step of halogenating the compound represented by formula (VII) in the presence or absence of a base to produce a compound represented by formula (VIII). The leaving group represented by L ₃ in the general formula (VIII) is a chlorine atom, a bromine atom or an iodine atom. This step can be performed using N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, iodine, etc. The solvent is not particularly limited as long as it does not hinder the reaction. Examples include acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide, and N,N-dimethylacetamide. , N-methyl-2-pyrrolidone and other appropriate solvents that have no hindrance to the reaction. Usable bases include organic bases such as diisopropylethylamine, pyridine, and tetrabutylammonium fluoride; or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, Potassium phosphate, sodium phosphate, potassium tertbutyrate, etc. The reaction temperature is usually 0°C to 100°C, preferably room temperature to reflux temperature. The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 24 hours.

(Step 5) This step is a method of producing a compound represented by general formula (IX) by reacting a compound represented by general formula (VIII) with ammonia or a salt thereof. The amount of ammonia or its salt used in this step is usually equimolar to excess mole relative to 1 mole of the compound represented by general formula (VIII). The reaction solvent is not particularly limited as long as it does not hinder the reaction. For example, water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethyl Formamide, N-methylpyrrolidone, dimethyltrisoxide, etc. or their mixed solvents, etc. The reaction temperature is usually 0°C to 200°C, preferably 70°C to 120°C. The reaction time is usually 5 minutes to 7 days, preferably 1 hour to 24 hours.

(Step 6) This step is a method of producing the compound represented by structural formula (X) from the compound represented by structural formula (IX) under acidic conditions. Examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. The amount of acid used is 1 mole to an excess, preferably 1 mole to 100 moles, based on 1 mole of the compound represented by structural formula (IX). The solvent used in the reaction may be one that does not adversely affect the reaction. For example, water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane can be used. alkane, dimethyl formamide, N-methylpyrrolidone, dimethyl styrene, etc. or mixtures thereof. The reaction temperature is usually 0°C to 200°C, preferably 25°C to 80°C. The reaction time is usually 5 minutes to 7 days, preferably 1 hour to 24 hours.

(Step 7) This step is a method for producing the compound represented by the structural formula (XII) by performing a coupling reaction between the compound represented by the general formula (X) and 3-quinolineboronic acid. This step can be carried out according to commonly known methods (for example, Chemical Reviews, Vol. 95, p2457, 1995). For example, it can be carried out in the presence of a transition metal catalyst and a base in a solvent that does not adversely affect the reaction. The usage amount of 3-quinolineboronic acid is 1 to 10 moles per 1 mole of the compound represented by the general formula (X), and preferably 1 to 3 moles. As a transition metal catalyst, for example, a palladium catalyst (such as palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphine)ferrocene-palladium dichloride) can be used (II), etc.), nickel catalysts (such as nickel chloride, etc.), ligands (such as triphenylphosphine, tri-tert-butylphosphine, etc.) can also be added as needed, and metal oxides (such as copper oxide, Silver oxide, etc.) as a co-catalyst. The usage amount of the transition metal catalyst varies depending on the type of catalyst. It is usually 0.0001 to 1 mole, preferably 0.01 to 0.5 mole, based on 1 mole of the compound represented by the general formula (X). The usage amount is usually 0.0001 to 4 moles, preferably 0.01 to 2 moles, relative to 1 mole of the compound represented by the general formula (X). The usage amount of the cocatalyst is relative to 1 mole of the compound represented by the general formula (X). 1 mole of compound, usually 0.0001 to 4 moles, preferably 0.01 to 2 moles. Examples of the base include organic amine compounds (such as trimethylamine, triethylamine, diisopropylethylamine, etc.), alkali metal salts (such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, Potassium phosphate, sodium hydroxide, etc.), metal hydrides (such as potassium hydride, sodium hydride, etc.), alkali metal alkoxides (such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The usage amount of the base is usually 0.1 to 10 moles, preferably 1 to 5 moles, based on 1 mole of the compound represented by the general formula (X). The solvent may be one that does not adversely affect the reaction. Examples include hydrocarbon solvents (such as benzene, toluene, xylene, etc.) and halogenated hydrocarbon solvents (such as chloroform, 1,2-dichloroethane, etc.) , Nitrile solvents (such as acetonitrile, etc.), ether solvents (such as 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), alcohol solvents (such as methanol, ethanol, etc.), non- Protic polar solvents (such as dimethylformamide, dimethylstyrene, etc.), water or mixtures thereof, etc. The reaction temperature is usually 0°C to 200°C, preferably 60°C to 120°C. The reaction time is usually 5 minutes to 7 days, preferably 1 hour to 24 hours.

(Step 8) This step is a step of producing a compound represented by formula (XIV) by reacting a compound represented by formula (XII) and a compound represented by formula (XIII). The leaving group represented by L ₄ in the general formula (XIII) is a hydrogen atom or an acetyl group. This step can be carried out according to commonly known methods (for example, Synthetic Communications, Vol. 19, p561, 19895). For example, it can be carried out in the presence of a base and in a solvent that does not adversely affect the reaction. Examples of the base include alkali metal salts (such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, etc.), metal hydrides (such as potassium hydride, sodium hydride, etc.), and alkali metal alkanes. Oxides (such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The solvent is any solvent as long as it does not adversely affect the reaction. Examples include hydrocarbon solvents (such as benzene, toluene, xylene, etc.), nitrile solvents (such as acetonitrile, etc.), and ether solvents (such as 1,2- Dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), alcoholic solvents (such as methanol, ethanol, etc.), aprotic polar solvents (such as dimethylformamide, dimethyltrisoxide, etc.) ), water or mixtures thereof, etc. The reaction temperature is usually -100°C to 100°C, preferably -78°C to 50°C. The reaction time is usually 5 minutes to 7 days, preferably 1 hour to 24 hours.

[Manufacturing method 2] [Chemical 8] [In the formula, Y represents NH or O, P ₁ represents a hydrogen atom or a protecting group for an amine group, L ₅ , L ₆ and L ₇ represent leaving groups, R ₁ , ring A and n are synonymous with the above]

(Step 9) This step is a method of producing a compound represented by general formula (XVII) by reacting a compound represented by general formula (XV) and a compound represented by general formula (XVI) in the presence of a base. The leaving group represented by L ₅ in the general formula (XV) is a fluorine atom or a chlorine atom. The compounds represented by general formulas (XV) and (XVI) can be commercially available or can be produced according to known methods. The compound represented by the general formula (XVI) can be used in an amount of 1 to 10 moles, preferably 1 to 3 moles, per 1 mole of the compound represented by the general formula (XV). The base used in this step can be, for example, triethylamine, diisopropylethylamine, pyridine and other organic bases; or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium phosphate, etc. Potassium tributyrate and other inorganic bases. The amount of the base used is usually 1 mole to excess mole, preferably 1 to 3 mole, based on 1 mole of the compound represented by the general formula (XV). The reaction solvent is not particularly limited as long as it does not hinder the reaction, and suitable examples include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylstyrene, dimethylformamide, N-methylpyrrolidone, etc., methanol, ethanol, isopropyl alcohol or their mixed solvents, etc. The reaction temperature is usually 0°C to 200°C, preferably 50°C to 120°C. The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.

(Step 10) This step is a step of halogenating the compound represented by formula (XVII) in the presence or absence of a base to produce a compound represented by formula (XVIII). The leaving group represented by L ₆ in the general formula (XVIII) is a chlorine atom, a bromine atom or an iodine atom. This step can be performed using N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, iodine, etc. The solvent is not particularly limited as long as it does not hinder the reaction. For example, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone can be used. The reaction can be carried out in an appropriate solvent that will not hinder the reaction. Usable bases include organic bases such as diisopropylethylamine, pyridine, and tetrabutylammonium fluoride; or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, Potassium phosphate, sodium phosphate, potassium tertbutyrate, etc. The reaction temperature is usually 0°C to 100°C, preferably room temperature to reflux temperature. The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 24 hours.

(Step 11) This step is a method of producing a compound represented by general formula (XIX) by reacting a compound represented by general formula (XVIII) with ammonia or a salt thereof. The amount of ammonia or its salt used in this step is usually equimolar to excess mole relative to 1 mole of the compound represented by general formula (XVIII). The reaction solvent is not particularly limited as long as it does not hinder the reaction. For example, water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethyl Methanamide, N-methylpyrrolidone, dimethylstyrene, etc. or their mixed solvents, etc. The reaction temperature is usually 0°C to 200°C, preferably 70°C to 120°C. The reaction time is usually 5 minutes to 7 days, preferably 1 hour to 24 hours.

(Step 12) This step is a method of producing the compound represented by the structural formula (XXI) by performing a coupling reaction between the compound represented by the general formula (XIX) and 3-quinolineboronic acid (general formula (XX)). This step can be carried out according to commonly known methods (for example, Chemical Reviews, Vol. 95, p2457, 1995). For example, it can be carried out in the presence of a transition metal catalyst and a base in a solvent that does not adversely affect the reaction. The usage amount of 3-quinolineboronic acid is 1 to 10 moles, preferably 1 to 3 moles, based on 1 mole of the compound represented by the general formula (XIX). As a transition metal catalyst, for example, a palladium catalyst (such as palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphine)ferrocene-palladium dichloride) can be used (II), Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1' -biphenyl)] palladium (II), etc.), nickel catalysts (such as nickel chloride, etc.), etc., and ligands (such as triphenylphosphine, tri-tert-butylphosphine, etc.) can also be added as needed, using metal oxidation substances (such as copper oxide, silver oxide, etc.) as co-catalysts. The usage amount of the transition metal catalyst varies depending on the type of catalyst. It is usually 0.0001 to 1 mole, preferably 0.01 to 0.5 mole, based on 1 mole of the compound represented by the general formula (XIX). The usage amount of the cocatalyst is relative to 1 mole of the compound represented by the general formula (XIX), usually 0.0001 to 4 moles, preferably 0.01 to 2 moles, and the usage amount of the cocatalyst is relative to the general formula (XIX) Per mole of the compound represented by (XIX), it is usually 0.0001 to 4 moles, preferably 0.01 to 2 moles. Examples of the base include organic amine compounds (such as trimethylamine, triethylamine, diisopropylethylamine, etc.), alkali metal salts (such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, Potassium phosphate, sodium hydroxide, etc.), metal hydrides (such as potassium hydride, sodium hydride, etc.), alkali metal alkoxides (such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The usage amount of the base is usually 0.1 to 10 moles, preferably 1 to 5 moles, based on 1 mole of the compound represented by the general formula (XIX). The solvent may be one that does not adversely affect the reaction. Examples include hydrocarbon solvents (such as benzene, toluene, xylene, etc.) and halogenated hydrocarbon solvents (such as chloroform, 1,2-dichloroethane, etc.) , Nitrile solvents (such as acetonitrile, etc.), ether solvents (such as 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), alcohol solvents (such as methanol, ethanol, etc.), non- Protic polar solvents (such as dimethylformamide, dimethylstyrene, etc.), water or mixtures thereof, etc. The reaction temperature is usually 0°C to 200°C, preferably 60°C to 120°C. The reaction time is usually 5 minutes to 7 days, preferably 1 hour to 24 hours.

(Step 13) This step is a step of halogenating the compound represented by formula (XXI) in the presence or absence of a base to produce a compound represented by formula (XXII). The leaving group represented by L ₇ in the general formula (XXII) is a chlorine atom, a bromine atom or an iodine atom. This step can be performed using N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, iodine, etc. The solvent is not particularly limited as long as it does not hinder the reaction. For example, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone can be used. The reaction can be carried out in an appropriate solvent that will not hinder the reaction. Usable bases include organic bases such as diisopropylethylamine, pyridine, and tetrabutylammonium fluoride; or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, Potassium phosphate, sodium phosphate, potassium tertbutyrate, etc. The reaction temperature is usually 0°C to 100°C, preferably room temperature to reflux temperature. The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 24 hours.

(Step 14) This step is a step for producing the compound represented by formula (XXIV) by the zodiac reaction of the compound represented by formula (XXII) and the compound represented by formula (XXIII). As a method for the Nagoya reaction, a generally known method (for example, a method described in Chemical Reviews, Vol. 107, p. 874 (2007)) can be used, or a method based on the method can be used. For example, it can be carried out using a transition metal catalyst and In the presence of a base, the reaction is carried out in a solvent that does not adversely affect the reaction. As the transition metal catalyst, for example, palladium catalysts (such as palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichloro[1,1 '-Bis(diphenylphosphine)ferrocene]palladium, tris(dibenzylideneacetone)dipalladium(0), etc.), copper catalyst (such as copper bromide, copper iodide, etc.), etc. The amount of the transition metal catalyst that can be used is suitably in the range of 0.001 to 1 mole per 1 mole of the compound represented by formula (XXII). If necessary, as palladium ligands, triphenylphosphine, tris(2-furyl)phosphine, 1,1'-bis(diphenylphosphine)ferrocene, 4,5-bis(diphenyl)phosphine can be used Phosphine)-9,9'-dimethyl𠮿 , 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-di- tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, etc. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. Examples include: tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and N,N-dimethyl. Formamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, benzene, toluene, acetonitrile, dimethylsulfoxide, water, or mixed solvents thereof. In this step, as the base, organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine can be used; or sodium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate. , sodium hydroxide, sodium hydride, potassium phosphate, sodium phosphate, potassium tertbutyrate and other inorganic bases. The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours. The reaction temperature is usually 25°C to 200°C, preferably 30°C to 100°C.

[Manufacturing method 3] [Chemical 9] [In the formula, Y represents NH, P ₁ represents the protecting group of the amine group, and ring A, R ₁ and n are synonymous with the above]

(Step 15) This step is a step of removing the protection of the amine group of the compound represented by formula (XXIV) to produce the compound represented by formula (XXV). As a method for deprotection, generally known methods can be used, such as the method described in Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons (1981), or a method based thereon. When using tert-butoxycarbonyl group as a protecting group, deprotecting reagents include hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, etc. The usage amount of the reagent is preferably 1 to 100 moles based on 1 mole of compound (XXIV). The solvent used in the reaction may be one that does not adversely affect the reaction. For example, water, methanol, ethanol, dichloromethane, chloroform, etc. or a mixed solvent thereof may be used. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 80°C. The reaction time is usually 5 minutes to 7 days, preferably 1 hour to 48 hours.

[Manufacturing method 4] [Chemical 10] [In the formula, ring A, R ₁ , R ₂ , R ₃ and n are synonymous with the above]

(Step 16) This step is to produce the compound of the present invention represented by the general formula (XXVI) through the chelation reaction of the compound represented by the general formula (XXV) and carboxylic acid or acyl halide, acid anhydride, isocyanate, isothiocyanate or amine. Compound Methods. The above-mentioned chelation reagent is used in an amount of 0.5 to 10 moles, preferably 1 to 3 moles, based on 1 mole of the compound represented by the general formula (XXV). In addition, the chelation reagent can be a commercially available product or can be produced according to a known method. The reaction solvent is not particularly limited as long as it does not hinder the reaction. For example, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl Acetamide, N-methylpyrrolidin-2-one, dimethylstyrene, etc. or their mixed solvents, etc. The reaction temperature is usually -78 to 200°C, preferably 0 to 70°C. The reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours. The reaction can use a condensing agent as necessary. Examples of the condensing agent include: diphenylphosphoryl azide, N,N'-dicyclohexylcarbodiimide, benzotriazol-1-yl-oxy-tri- Dimethylaminophosphonium salt, 4-(4,6-dimethoxy-1,3,5-tri𠯤-2-yl)-4-methyl𠰌line hydrochloride, 1-ethyl-3 -(3-dimethylaminopropyl)carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole Combination, 2-chloro-1,3-dimethylimidazoline hydrochloride, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylhexane Urea onium hexafluorophosphate, carbonyl diimidazole, etc.

In addition, a base may be added to the above reaction as necessary. Examples of the base include triethylamine, diisopropylethylamine, pyridine, lutidine, trimethylpyridine, 4-(N,N-dimethylamino)pyridine, and tertbutylamine. Potassium acid, sodium tertbutyrate, sodium methoxide, sodium ethoxide, lithium bis(trimethylsilane)amide, sodium bis(trimethylsilane)amide, potassium bis(trimethylsilane)amide, butyl Organic bases such as lithium; or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. The amount to be added is 1 to 100 moles, preferably 1 to 10 moles, based on 1 mole of the compound represented by general formula (XXV). In addition, in this step, the compound represented by the general formula (XXV) can be reacted with an alkyl halide in the presence of a base to produce the compound represented by the general formula (XXVI). The alkyl halide is used in an amount of 0.5 to 10 moles, preferably 1 to 3 moles, based on 1 mole of the compound represented by the general formula (XXV). In addition, a commercially available product can be used for this alkyl halide, or it can be produced according to a known method. The reaction solvent is not particularly limited as long as it does not hinder the reaction. For example, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl Acetamide, N-methylpyrrolidin-2-one, dimethylstyrene, etc. or their mixed solvents, etc. Examples of the base include triethylamine, diisopropylethylamine, pyridine, lutidine, trimethylpyridine, 4-(N,N-dimethylamino)pyridine, and tertbutylamine. Potassium acid, sodium tertbutyrate, sodium methoxide, sodium ethoxide, lithium bis(trimethylsilane)amide, sodium bis(trimethylsilane)amide, potassium bis(trimethylsilane)amide, butyl Organic bases such as lithium; or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. The amount to be added is 1 to 100 moles, preferably 1 to 10 moles, based on 1 mole of the compound represented by general formula (XXV). The reaction temperature is usually -78 to 200°C, preferably 50 to 100°C. The reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours. In addition, this step can also produce the compound represented by the general formula (XXVI) by subjecting the compound represented by the general formula (XXV) and an aldehyde reagent to a reductive amination reaction in the presence of a reducing agent.

The aldehyde reagent is used in an amount of 0.5 to 10 moles, preferably 1 to 3 moles, based on 1 mole of the compound represented by the general formula (XXV). In addition, the aldehyde reagent can be commercially available or can be produced according to a known method. The reducing agent is not particularly limited, and examples thereof include hydrogenated metal complexes, such as sodium borohydride, sodium cyanoborohydride, triacetyloxyborohydride, and the like, ranging from 0.1 molar to a large excess. Additives can also be added to the reaction as needed, including: acids, bases, inorganic salts or organic salts, etc., such as 0.01 mol to a large excess of trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, potassium carbonate, sodium hydroxide, lithium hydroxide , sodium sulfate, magnesium sulfate, tetraisopropyl orthotitanate, zinc chloride, etc. The reaction solvent is not particularly limited as long as it does not hinder the reaction. For example, toluene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and dimethylacetyl are suitable. Amine, N-methylpyrrolidin-2-one, dimethylstyrene, methanol, ethanol, 2-propanol, tert-butanol, etc. or their mixed solvents, etc. The reaction temperature is usually -78 to 200°C, preferably 0 to 60°C. The reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.

When the compound of the present invention has isomers such as optical isomers, stereoisomers, rotamers, and tautomers, any isomer and a mixture thereof are included unless otherwise specified. among the compounds of the present invention. For example, when an optical isomer exists in the compound of the present invention, the racemate and the optical isomer separated from the racemate are also included in the compound of the present invention unless otherwise specified. The salt of the compound of the present invention means a pharmaceutically acceptable salt, and examples thereof include base addition salts and acid addition salts.

The compound of the present invention or its salt may be amorphous or crystalline. Whether the crystalline form is a single crystalline form or a polymorphic mixture, it is included in the compound of the present invention or its salt. Crystals can be produced by crystallizing using a known crystallization method. The compound of the present invention or a salt thereof may be a solvate (such as a hydrate, etc.) or an unsolvated compound, and both are included in the compound of the present invention or a salt thereof. Compounds labeled with isotopes (such as ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) are also included in the compounds or salts thereof of the present invention.

When the compound of the present invention or its salt is used as medicine, a pharmaceutically acceptable carrier may be formulated as necessary, and various administration forms may be adopted according to the purpose of prevention or treatment. As such forms, for example, oral preparations, injections, suppositories, and ointments may be used. Any agent, patch, etc., preferably an oral agent. These administration forms can be produced using commonly used preparation methods known in the industry. One embodiment of the present invention provides an antitumor agent containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. In one embodiment of the present invention, the anti-tumor agent is an anti-tumor agent for oral administration. Furthermore, one embodiment of the present invention provides a method for preventing and/or treating tumors, which includes administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof. Furthermore, one embodiment of the present invention provides a method for preventing and/or treating tumors, which includes orally administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof. Furthermore, one embodiment of the present invention provides a use of the compound of the present invention or a pharmaceutically acceptable salt thereof for producing an anti-tumor agent. Furthermore, one embodiment of the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for producing an anti-tumor agent for oral administration. Furthermore, one embodiment of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention and/or treatment of tumors. Furthermore, one embodiment of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for oral administration to prevent and/or treat tumors.

In this specification, the term "effective amount" of the compound of the present invention refers to the biological or medical response of the subject, such as reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating the state, slowing or delaying the development of disease, or preventing The amount of the compound of the present invention (therapeutic effective amount) for diseases, etc. In this specification, the term "subject" includes mammals and non-mammals. Examples of mammals are not limited, but include: humans, chimpanzees, great apes, monkeys, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, hedgehogs, kangaroos, moles Rat, wild boar, bear, tiger, lion, etc. Examples of non-mammals are not limited and may include: birds, fish, reptiles, etc. In one embodiment, the subject is a human being, and may also be a human being whose diagnosis requires treatment of the symptoms, conditions, or diseases disclosed in this specification.

One aspect of the present invention provides a pharmaceutical composition containing the compound of the present invention or a salt thereof. A pharmaceutical composition according to one embodiment of the present invention includes a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Furthermore, one embodiment of the present invention provides a use of the compound of the present invention or a salt thereof for producing a pharmaceutical composition. Another embodiment of the present invention provides a compound of the present invention or a salt thereof for use as medicine.

When the compound of the present invention or its salt is used as medicine, a pharmaceutically acceptable carrier may be formulated as necessary, and various administration forms may be adopted according to the purpose of prevention or treatment. As such forms, for example, oral preparations, injections, suppositories, and ointments may be used. Any agent, patch, etc., preferably an oral agent. These administration forms can be produced using commonly used preparation methods known in the industry.

As pharmaceutically acceptable carriers, various organic or inorganic carrier substances commonly used as raw materials for preparations can be used to formulate excipients, binding agents, disintegrants, lubricants, coating agents, colorants, etc. in solid preparations. Solvents, solubilizers, suspending agents, isotonic agents, buffers, analgesics, etc. in liquid preparations. In addition, preparation additives such as preservatives, antioxidants, sweeteners, and stabilizers may also be used as necessary.

When preparing a solid preparation for oral use, excipients are added to the compound of the present invention, and a binding agent, a disintegrating agent, a lubricant, a coloring agent, a flavoring/flavoring agent, etc. may be added if necessary, and then the preparation can be produced by a conventional method. Tablets, coated tablets, granules, powders, capsules, etc. When preparing injections, a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. can be added to the compound of the present invention, and subcutaneous, intramuscular, and intravenous injections can be produced by conventional methods.

The amount of the compound of the present invention to be formulated in each of the above-mentioned dosage unit forms is not fixed depending on the symptoms of the target to which it should be applied, the dosage form, etc., but is generally preferably 0.05 to 0.05 for the oral dosage form per dosage unit form. 1000 mg, injection is set to 0.01 to 500 mg, and suppository is set to 1 to 1000 mg. In addition, the daily dosage of pharmaceuticals having the above-mentioned administration forms varies depending on the subject's symptoms, weight, age, gender, etc., and cannot be determined uniformly. However, as long as the compound of the present invention is used, it is usually set as an adult (body weight 50 kg) 0.05 to 5000 mg per day, preferably 0.1 to 1000 mg.

Tumors targeted by the present invention are not particularly limited, and examples thereof include: head and neck cancer, gastrointestinal cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder, bile duct cancer, etc.), pancreatic cancer, and colorectal cancer) (Colorectal cancer, colon cancer, rectal cancer, anal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma (pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, testicular mesothelioma, etc.) skin tumors, etc.), breast cancer, reproductive organ cancer (ovarian cancer, vulva cancer, uterine cancer (cervical cancer, uterine corpus cancer, endometrial cancer, etc.), etc.), urinary system cancer (kidney cancer, bladder cancer, prostate cancer , testicular cancer, urothelial cancer, renal pelvis cancer, urethra cancer, etc.), hematopoietic system tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, rhabdomyosarcoma, skin cancer, brain tumors, malignant nerves Sheath tumors, neuroendocrine tumors, thyroid cancer, etc. Preferred are head and neck cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer, and brain tumors, and lung cancer is particularly preferred. Furthermore, here, cancer includes not only primary lesions but also cancers that have metastasized to other organs (liver, etc.). Furthermore, the compound of the present invention or its salt has excellent inhibitory activity against variant EGFR. Examples of such mutant EGFR include drug-resistant mutant EGFR and highly sensitive mutant EGFR. Therefore, the compound of the present invention or its salt is also useful as an anti-tumor agent for the above-mentioned malignant tumors with variant EGFR.

The compound of one aspect of the present invention or its salt has excellent EGFR inhibitory activity. Among them, it has excellent inhibitory activity against EGFR (Del19/C797S), EGFR (L858R/C797S), EGFR (Del19/T790M/C797S) or EGFR (L858R/T790M/C797S), and is useful as an antitumor agent. In addition, it has the following advantages: it has excellent selectivity for mutant EGFR and has fewer side effects caused by wild-type EGFR or other kinases.

In this specification, "wild-type EGFR" is represented by the amino acid sequence of GenBank accession number: NP_005219.2, for example. In this specification, "penetrance factor 19" refers to the region 729-823 in the amino acid sequence of wild-type EGFR (for example, GenBank accession number: NP_005219.2).

In this specification, "Del19" refers to a mutation resulting from the deletion of one or more amino acids in the epigenetic factor 19 region of wild-type EGFR. In addition to deletions in this region, mutations resulting from the insertion of one or more arbitrary amino acids are also included. As the deletion mutation of penetrant factor 19, it shows the mutation of deletion of five amino acids from glutamic acid to 750th alanine in the penetrant factor 19 region (Del E746-A750 (or also known as d746-750) ); a mutation resulting from the deletion of seven amino acids from leucine to proline 753 in the region of penetrance factor 19 (Del 747-P753insS); the mutation in the region of penetrance factor 19 Variation with deletion of 5 amino acids from leucine 747 to 751 threonine (Del L747-T751); 4 amines from leucine 747 to 750 alanine in the penetrance factor 19 region Variation resulting from deletion of amino acid and insertion of proline (Del 747-A750insP), etc. Preferably, a mutation in which five amino acids are deleted from glutamine 746 to alanine 750 in the penetrance factor 19 region (Del E746-A750) can be cited.

Examples and test examples are shown below to explain the present invention in more detail. However, the present invention is not limited to these Examples. Unless otherwise noted, commercially available reagents used in the examples were used. In silica column chromatography and alkaline silica column chromatography, prepacked columns manufactured by Shoko Scientific or Biotage are used. The reverse phase preparative HPLC (high performance liquid chromatography, high performance liquid chromatography) column chromatography method is implemented under the following conditions. Implement by appropriately setting the injection volume and gradient. Column: CAPCELL PAK C18 MGIII manufactured by OSAKA SODA, 30×50 mm, 5 μm UV detection: 254 nm Column flow rate: 40 mL/min Mobile phase: water/acetonitrile (0.1% formic acid) Injection volume: 0.1-1.0 mL Gradient water/acetonitrile 10%→90% (7 minutes) The NMR spectroscopy system uses AL400 (400 MHz; Japan Electronics (JEOL)), Mercury400 (400 MHz; Agilent Technologies), AVANCE NEO (400 MHz; Bruker), AVANCE III HD (500 MHz; Bruker) type spectrometers, in deuterated solvents When tetramethylsilane is included in , tetramethylsilane is used as an internal reference. Otherwise, an NMR solvent is used as an internal reference for measurement, and the total δ value is expressed in ppm. In addition, the LCMS (liquid chromatography-mass spectrometry, liquid chromatography mass spectrometry) spectrum system was measured under the following two conditions using SQD manufactured by Waters Corporation, and the [M+H]+ value was shown. MS detection: ESI positive UV detection: 254 and 210 nm Column flow rate: 0.5 mL/min Mobile phase: water/acetonitrile (0.1% formic acid) Injection volume: 1 μL Column: Acquity BEH, 2.1×50 mm, 1.7 μm gradient: Time (min) Water/acetonitrile (0.1% formic acid) 0 95 5 0.1 95 5 2.1 5 95 3.0 STOP The meaning of the abbreviations is shown below. s: single peak d: Twin Peaks t: Triplet q: quartet dd: double twin peaks m: multiple peaks br: broad peak brs: broad single peak DMSO-d6: Deuterated dimethylsulfoxide CDCl3: deuterated chloroform THF: Tetrahydrofuran DMF: N,N-dimethylformamide DMA: N,N-dimethylacetamide DME: 1,2-dimethoxyethane DMSO: dimethylsulfoxide HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylhexaureonium hexafluorophosphate DIPEA: Diisopropylethylamine TBAF: tetrabutylammonium fluoride NMP: N-methylpyrrolidin-2-one DMPU: N,N-dimethylpropyl urea WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBT: 1-Hydroxybenzotriazole NBS: N-bromosuccinimide

[Production Example 1] Production of 7-(4- aminobicyclo [2.2.1] heptan -1- yl )-6- ethynyl- 5-( quinolin- 3- yl )-7H- pyrrolo [2, 3-d] pyrimidin -4- amine (step 1) Combine 4,6-dichloro-5-iodopyrimidine (0.38 g), (4-aminobicyclo[2.2.1]heptan-1-yl)amine A mixture of tert-butyl formate (0.30 g), DIPEA (0.69 ml), and THF (3 ml) was stirred at 70°C overnight. After the reaction mixture was cooled to room temperature, it was concentrated. The obtained residue was purified by silica gel column chromatography to obtain (4-((6-chloro-5-iodopyrimidin-4-yl)amino)bicyclo[2.2.1]heptan-1-yl) Tert-butyl carbamate (Production Example (1-1)).

(step 2) The compound of Production Example (1-1) (390 mg), tris(2-furyl)phosphine (39 mg), tris(dibenzylideneacetone)dipalladium (0) (38 mg), copper iodide ( A mixture of I) (32 mg), propargyl aldehyde diethyl acetal (0.24 ml), DIPEA (0.22 ml), and DMF (5.9 ml) was stirred at 70°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain (4-((6-chloro-5-(3,3-diethoxypropyn-1-yl)pyrimidin-4-yl)amine tert-butyl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-2)).

(step 3) A mixture of the compound of Production Example (1-2) (325 mg), TBAF (THF solution, 1 M, 0.7 ml), and THF (3.5 ml) was stirred at 70° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain (4-(4-chloro-6-(diethoxymethyl)-7H-pyrrole) Para[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-3)).

(Step 4) To a mixture of the compound of Production Example (1-3) (329 mg) and DMF (3.3 ml), NBS (72 mg) was added at room temperature, and the mixture was stirred for 1 hour. A saturated sodium sulfite aqueous solution was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography to obtain (4-(5-bromo-4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d] Pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamic acid tert-butyl ester (Production Example (1-4)).

(Step 5) A mixture of the compound of Production Example (1-4) (358 mg), DME (2 ml), and ammonia water (2 ml) was placed in a pressure-resistant reaction vessel, and stirred at 90° C. for 12 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and then the organic layer was concentrated. THF (1.8 ml), acetic acid (1.8 ml), and water (0.4 ml) were added to the obtained residue, and the mixture was stirred at 45°C for 16 hours. After the reaction mixture was concentrated, it was neutralized with a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography to obtain (4-(4-amino-5-bromo-6-formyl-7H-pyrrolo[2,3-d]pyrimidine-7- tert-butyl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-5)).

(Step 6) The compound of Production Example (1-5) (4.1 g), 3-quinolineboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium (0) (460 mg), sodium carbonate (2.1 g), DME ( A mixture of 4 ml) and water (21 ml) was heated and circulated under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography to obtain (4-(4-amino-6-formyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamic acid tert-butyl ester (Production Example (1-6)).

(Step 7) The compound of Production Example (1-6) (3.9 g), dimethyl (1-diazo-2-oxypropyl)phosphonate (4.8 ml), potassium carbonate (3.3 g), and methanol (60 ml) were mixed The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography to obtain (4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamic acid tert-butyl ester (Production Example (1-7)).

(Step 8) Trifluoroacetic acid (40 ml) was added to a solution of the compound of Production Example (1-7) in methylene chloride (40 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with water, neutralized with an aqueous sodium hydroxide solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by alkaline silica column chromatography to obtain the title compound (7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine).

[Production Example 2] Production of 7-(4- aminobicyclo [2.2.2] octane -1- yl )-6- ethynyl- 5-( quinolin- 3- yl )-7H- pyrrolo [2, 3-d] pyrimidin -4- amine used (4-aminobicyclo[2.2.2]octane-1-yl)carbamic acid tert-butyl ester instead of the (4-amine used in step 1 of Production Example 1 The above-mentioned title compound (7- (4-Aminobicyclo[2.2.2]octane-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4- amine).

[Production Example 3] Production of (4-(4- amino -6- bromo -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2 .1] tert-butyl heptan -1- yl ) carbamate (step 1) Combine 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (4.6 g), (4-aminobicyclo [2.2.1] A mixture of tert-butyl heptan-1-yl)carbamate (5.0 g), DIPEA (7.7 ml), and acetonitrile (50 ml) was stirred at 100°C for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated. After diluting with ethyl acetate (50 ml) and water (10 ml), the insoluble matter was filtered. The organic layer was washed with a saturated brine ammonium chloride aqueous solution and then with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain crude (4-(4-chloro-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamic acid tert-butyl ester (Production Example (3-1)).

(step 2) To the NMP (50 ml) solution of the compound of Production Example (3-1), NBS (4.3 g) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes. Slowly add saturated sodium sulfite aqueous solution (5 ml) and water (100 ml) to the reaction mixture, and stir for 10 minutes. The generated solid was filtered and washed with water to obtain (4-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1] Heptan-1-yl)carbamic acid tert-butyl ester (Production Example (3-2)).

(step 3) A mixture of the compound of Production Example (3-2) (11.1 g), DME (110 ml), and ammonia water (55 ml) was placed in a pressure-resistant reaction vessel, and stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, water (150 ml) was added, and stirred for 30 minutes. The generated solid was filtered and washed with water to obtain (4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1 ] Heptan-1-yl)carbamic acid tert-butyl ester (Production Example (3-3)).

(Step 4) The compound of Production Example (3-3) (4.3 g), 3-quinolineboronic acid (2.1 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (240 mg), sodium carbonate (2.2 g), THF (44 ml), water ( 22 ml) mixture was heated and circulated under nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate (44 ml) and saturated aqueous sodium bicarbonate solution (10 ml) were added, and the mixture was stirred overnight. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography. The solid obtained was suspended in acetonitrile (25 ml) and circulated with heating for 5 hours and cooled to 0°C. The solid was filtered and washed with acetonitrile to obtain (4-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) bicyclo [2.2.1] Heptan-1-yl)carbamic acid tert-butyl ester (Production Example (3-4)).

(Step 5) To a solution of the compound (60 mg) in Production Example (3-4) in THF (2 ml), NBS (25 mg) was added at 0°C, and the mixture was stirred for 15 minutes. 5% sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica column chromatography to obtain (4-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamic acid tert-butyl ester (Production Example (3-5)).

[Example 1] N-(4-(4- amino -6- ethynyl -5-( quinolin -3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptan -1- yl ) benzamide 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl- obtained in Production Example 1 To a solution of 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10 mg) in THF (1 ml) was added DIPEA (0.013 ml), and benzyl was added Chloride (0.006 ml). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The obtained residue was purified by silica column chromatography to obtain the title compound.

[Example 2] N-(4-(4- amino -6- ethynyl -5-( quinolin -3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptan -1- yl ) pyrimidin -5- methamide 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6- obtained in Production Example 1 To a solution of ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (7 mg) in THF (1 ml) was added DIPEA (0.013 ml) and pyrimidine -5-carboxylic acid (24 mg), and HATU (10 mg) was added. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The obtained residue was purified by reverse phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the title compound.

[Example 3] N-(4-(4- amino -6- ethynyl -5-( quinolin -3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo 7-( 4- aminobicyclo [2.2.1] heptan -1- yl ) -6 obtained from [2.2.1]heptan-1-yl)-4 - methamide in Production Example 1 To a solution of -ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (7 mg) in THF (1 ml), DIPEA (0.013 ml) was added. D-4-carboxylic acid (24 mg) was added, and HATU (10 mg) was added. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The obtained residue was purified by silica column chromatography to obtain the title compound.

[Example 4] 2-((4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) Bicyclo [2.2.1] heptan -1- yl ) amino ) acetonitrile 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl obtained in Production Example 1 -To a mixed solution of 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10 mg) in THF (1 ml) and acetonitrile (1 ml), DIPEA was added (0.013 ml), bromoacetonitrile (0.003 ml). Stir at room temperature for 1 hour and at 50°C overnight, and concentrate the reaction mixture. The obtained residue was purified by silica column chromatography to obtain the title compound.

[Example 5] 4-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-1- methylpiperidine - 2- one (step 1) 7-(4-aminobicyclo[2.2.1]heptane obtained in Production Example 1 -1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20 mg) in dichloromethane (0.5 ml) Triethylamine (0.011 ml) and methyl bromoacetate (0.005 ml) were added to the solution, and after stirring at room temperature overnight, water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified using alkaline silica gel column chromatography to obtain (4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)glycinate methyl ester. (Step 2) (4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-) obtained in the above step 1 To a solution of 7-yl)bicyclo[2.2.1]heptan-1-yl)glycinate methyl ester in methanol (0.2 ml), add (2-oxyethyl)carbamic acid tert-butyl methyl ester (0.01 ml), While stirring, add 0.5 M sodium cyanoborohydride-0.25 M zinc chloride methanol solution (0.3 ml) and stir at 60°C overnight. 0.5 M sodium cyanoborohydride-0.25 M zinc chloride methanol solution (0.3 ml) was added to the reaction mixture again, and the mixture was stirred for another day. After cooling to room temperature, trifluoroacetic acid (0.5 ml) was added and stirred for 3 days. After the reaction mixture was concentrated, it was neutralized with a saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by alkaline silica column chromatography to obtain the title compound.

[Example 6] N-(4-(4- amino -6- ethynyl -5-( quinolin -3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.2] octane -1- yl )-1- methyl -1H- pyrazole -5- carboxamide uses 7-(1-amino-4-bicyclo[2.2.2]octane-yl, respectively )-6-ethynyl-5-(quinolin-3-yl)pyrrolo[2,3-d]pyrimidin-4-amine and 1-methyl-1H-pyrazole-5-carboxylic acid chloride instead of examples 7-(4-Aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3] used in 1 Except for -d] pyrimidin-4-amine and benzyl chloride, the above-mentioned title compound was obtained by carrying out the same method as Example 1.

[Example 7] 4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2. 2] Octane -1- ol Use 4-aminobicyclo[2.2.2]octane-1-ol instead of (4-aminobicyclo[2.2.1]heptane used in Production Example 1 (Step 1) -1-yl)carbamic acid tert-butyl ester, the same method as in Production Example 1 (step 1-7) was carried out, thereby obtaining the above-mentioned title compound.

[Example 8] 6- ethynyl -7-(4-(( pyridin -3- ylmethyl ) amino ) bicyclo [2.2.2] octan -1- yl )-5-( quinoline -3- 7- (4- aminobicyclo [2.2.2] octane -1-yl)-6-yl) -7H- pyrrolo [2,3-d] pyrimidin-4 - amine obtained in Production Example 2 To a solution of ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10 mg) in THF (0.5 ml) was added potassium carbonate (17 mg), DIPEA (0.02 ml), 3-(chloromethyl)pyridine hydrochloride (20 mg). The reaction mixture was stirred at 80°C for 2 days. After cooling to room temperature, the mixture was purified by alkaline silica gel column chromatography to obtain the title compound.

[Example 9] 6- ethynyl- 7-(4- 𠰌 linylbicyclo [2.2.1] heptan -1- yl )-5-( quinolin- 3- yl )-7H- pyrrolo [2, 3-d] pyrimidin -4 - amine 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrole And[2,3-d]pyrimidin-4-amine (40 mg), DIPEA (0.11 ml), 1-bromo-2-(2-bromoethoxy)ethane (0.26 ml), DMF (5 ml) The mixture was stirred at 80°C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography and concentrated. The residue was washed with ethyl acetate to obtain the above-mentioned title compound.

[Example 10] (4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2 .1] Heptan -1- yl ) methanol Use (4-aminobicyclo[2.2.1]heptan-1-yl)methanol instead of the (4-aminobicyclo[2.2.1]heptan-1-yl)methanol used in Production Example 1 (Step 1) 2.2.1] Except for tert-butyl heptan-1-yl)carbamate, the same method as in Production Example 1 (Step 1-7) was carried out to obtain the above-mentioned title compound.

[Example 11] 7-(4-( dimethylamino ) bicyclo [2.2.1] heptan -1- yl )-6- ethynyl- 5-( quinolin- 3- yl )-7H- pyrrole 7-(4 - aminobicyclo [2.2.1]heptan- 1 -yl)-6-ethynyl-5- ([2,3-d] pyrimidin -4-amine obtained in Production Example 1 To a mixed solution of quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10 mg) in methanol (0.5 ml) and THF (0.5 ml), 37% formaldehyde aqueous solution (0.01 ml), add separately prepared 0.5 M sodium cyanoborohydride-0.25 M zinc chloride methanol solution (0.1 ml) and stir at room temperature for 30 minutes, then concentrate the reaction mixture. The obtained residue was purified by silica column chromatography to obtain the title compound.

[Example 12] (4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2 .1] Heptan -1- yl ) ethyl carbamate except that ethyl chloroformate was used instead of benzyl chloride used in Example 1, the same method as in Example 1 was carried out to obtain the above Title compound.

[Example 13] N-((4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) Bicyclo [2.2.1] heptan -1- yl ) methyl )-1- methyl -1H- pyrazole -5- carboxamide (step 1) obtained in Example 10 (4-(4- Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)methanol To a mixed solution of (200 mg) dichloromethane (4.9 ml) and THF (4.9 ml), add methanesulfonyl chloride (0.076 ml) and triethylamine (0.272 ml) in an ice bath. After stirring at room temperature for 1.5 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography and concentrated. The residue was washed with ethyl acetate to obtain (4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7- methyl)bicyclo[2.2.1]heptan-1-yl)methanesulfonate. (Step 2) (4-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1] A mixed solution of heptan-1-yl)methanesulfonate (139 mg), sodium azide (55 mg), and DMSO (5.7 ml) was stirred at 80°C for 24 hours, and then stirred at 60°C. Stir overnight. The reaction mixture was diluted with water, filtered, and the residue was washed with water. Triphenylphosphine (0.089 mg) was added to the THF solution (5.6 ml) of the obtained residue, and the mixture was stirred at 40° C. overnight. Water (0.10 ml) was added to the reaction mixture, stirred at 40°C for 6 hours, and the reaction mixture was concentrated. The obtained residue was purified by alkaline silica column chromatography to obtain 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5- (Quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. (Step 3) In 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo Add [2,3-d]pyrimidin-4-amine (5 mg), 1-methyl-1H-pyrazole-5-carboxylic acid (1.7 mg), and HATU (6.9 mg) in DMSO (0.5 ml). DIPEA (0.0064 ml), stir at room temperature for 1 hour. The reaction mixture was purified by reverse-phase HPLC to obtain the above-mentioned title compound.

[Example 14] N-((4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) Bicyclo [2.2.1] heptan -1- yl ) methyl )-5- methylpyridine - 2- carboxylic acid was used instead of 5-methylpyridine-2-carboxylic acid in Example 13 (step 3) Except for using 1-methyl-1H-pyrazole-5-carboxylic acid, the same method as in Example 13 (step 3) was carried out to obtain the above-mentioned title compound.

[Example 15] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptane -1- yl )-5- chloropyridine -2- methamide 7- (4-aminobicyclo[2.2.1]heptane-1- obtained in Production Example 1 To a solution of pyrrolo[2,3-d]pyrimidin-4-amine (5 mg) in DMF (1 ml) was added DIPEA ( 0.004 ml), 5-chloropyridine-2-carboxylic acid (5 mg), and add WSC (4 mg) and HOBT (3 mg). After stirring at 50° C. for 2 hours, the reaction mixture was purified by reverse-phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the above-mentioned title compound.

[Example 16] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-[1,2,4] triazolo [1,5-a] pyridine -6- methamide 7-(4-) obtained in Production Example 1 Aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(4 mg) in THF (1 ml), DMF (0.05 ml), DIPEA (0.006 ml) and [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (1.7 mg) were added , and add HATU (6 mg). After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The obtained residue was purified by silica column chromatography to obtain the title compound.

[Example 17] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-1-(2- methoxyethyl )-1H- pyrazole -5- methamide Use DMSO instead of THF used in Example 2, use 1- The above-mentioned title compound was obtained by carrying out the same method as Example 2 except that (2-methoxyethyl)-1H-pyrazole-5-carboxylic acid was substituted for pyrimidine-5-carboxylic acid.

[Example 18] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-1,2,3- thiadiazole -5- carboxamide Use 1,2,3-thiadiazole-5-carboxylic acid instead of that used in Example 17 Except for using 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid, the same method as in Example 17 was carried out to obtain the title compound.

[Example 19] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptan -1- yl )-1,2,4- tri -3- carboxamide uses 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6 -Ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine instead of the 7-(4-(amine) used in Example 13 (step 3) methyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine , using sodium 1,2,4-tri𠯤-3-carboxylate instead of 5-methylpyridine-2-carboxylic acid, except that the same method as in Example 13 (step 3) was carried out, thereby obtaining the above Title compound.

[Example 20] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-1- cyclopropyl -1H- pyrazole -5- carboxamide Use 1-cyclopropyl-1H-pyrazole-5-carboxylic acid instead of Example 17 Except for using 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid, the same method as in Example 17 was carried out to obtain the title compound.

[Example 21] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptan -1- yl )-1H- pyrazole -1- carboxamide 7-(4-aminobicyclo[2.2.1]heptan-1-yl obtained in Production Example 1 To a solution of )-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (9.5 mg) in DMF (0.4 ml) was added carbonyldiimidazole (8 mg) and stirred at room temperature for 1 hour. Pyrazole (5 mg) was added, and after stirring at room temperature overnight, water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica column chromatography to obtain the title compound.

[Example 22] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-1- methyl -1H-1,2,3- triazole -5- carboxamide uses 1-methyl-1H-1,2,3-triazole -5-carboxylic acid replaced 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17, except that the same method as in Example 17 was carried out. The above title compound was obtained.

[Example 23] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-1- methyl -1H- imidazole -2- carboxamide Use 1-methyl-1H-imidazole-2-carboxylic acid instead of 1 used in Example 17 -(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid, except that the same method as in Example 17 was carried out, thereby obtaining the above-mentioned title compound.

[Example 24] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-1- methyl -1H- pyrazole -5- carboxamide Use 1-methyl-1H-pyrazole-5-carboxamide chloride instead of what was used in Example 1 The above-mentioned title compound was obtained by carrying out the same method as Example 1 except using benzoyl chloride.

[Example 25] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-1- methyl -6- side oxy -1,6- dihydropyrimidine -5- methamide uses 1-methyl-6-side oxy-1 , 6-dihydropyrimidine-5-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17. In addition, the same procedure as in Example 17 was performed. The above-mentioned title compound was obtained by the same method.

[Example 26] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-1- phenyl -1H- pyrazole -5- carboxamide Use 1-phenyl-1H-pyrazole-5-carboxylic acid instead of that used in Example 17 Except for using 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid, the same method as in Example 17 was carried out to obtain the title compound.

[Example 27] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptan -1- yl )-2,2- difluoroacetamide in 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5 -(Quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (25 mg) in dichloromethane (2 ml), add 2,2- A solution of difluoroacetic anhydride (0.0079 ml) in dichloromethane (0.5 ml) was stirred in an ice bath for 1 hour. The reaction mixture was purified by silica gel column chromatography to obtain the above-mentioned title compound.

[Example 28] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-2- methoxyacetamide uses 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5- (Quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine replaced the 7-(4-(aminomethyl)bicyclo[ 2.2.1]Heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine using 2-methoxy Except that 5-methylpyrazoacetic acid was used instead of 5-methylpyridine-2-carboxylic acid, the same method as in Example 13 (step 3) was carried out, thereby obtaining the above-mentioned title compound.

[Example 29] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-3-( fluoromethyl )-1- methyl -1H- pyrazole -5- carboxamide (step 1) in potassium tert-butoxide (6.1 g) A mixed solution of 2-acetylfuran (3.0 g) and diethyl oxalate (8.0 g) in 1,2-dimethoxyethane (50 ml) was added to the THF (50 ml) suspension solution. After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure and 1 M hydrochloric acid (20 ml) was added. After extraction with ethyl acetate, the organic layer was washed with water and concentrated to obtain ethyl 4-(furan-2-yl)-2,4-bis-oxybutyrate. (Step 2) 1,1,1,3,3,3-hexane of 4-(furan-2-yl)-2,4-bis-oxybutyric acid ethyl ester (2.4 g) obtained in step 1 To a solution of fluoroisopropyl alcohol (25 ml), add methylhydrazine (1.1 ml) and stir at room temperature. After the reaction is completed, the reaction mixture is concentrated and the obtained residue is purified by silica gel column chromatography to obtain ethyl 5-(furan-2-yl)-1-methyl-1H-pyrazole-3-carboxylate. (Step 3) To a suspension solution of lithium aluminum hydride (0.5 g) in THF (10 ml), add 5-(furan-2-yl)-1-methyl-1H-pyrazole-3-carboxy under ice bath Ethyl acid ester (1.5 g). The reaction solution was stirred at 60°C. After the reaction was completed, it was cooled to room temperature, and saturated aqueous sodium sulfate solution (5 ml) was added. The residue was filtered, and the solution was concentrated and purified by silica column chromatography to obtain (5-(furan-2-yl)-1-methyl-1H-pyrazol-3-yl)methanol. (Step 4) To a solution of 5-(furan-2-yl)-1-methyl-1H-pyrazol-3-yl)methanol (0.16 g) in dichloromethane (2 ml), add Fluorinated bis(2-methoxyethyl)aminosulfate (0.34 ml). After stirring at room temperature for 1 hour, a saturated aqueous solution of sodium bicarbonate (1 ml) was added, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water. After concentrating the organic layer, the obtained residue was purified using silica gel column chromatography to obtain 3-(fluoromethyl)-5-(furan-2-yl)-1-methyl-1H-pyrazole. . (Step 5) Add 3-(fluoromethyl)-5-(furan-2-yl)-1-methyl-1H-pyrazole (62 mg) in acetonitrile (2 ml), carbon tetrachloride (2 ml ) and water (3 ml) were added to a mixed solution of sodium periodate (0.73 g) and ruthenium (III) chloride hydrate (5 mg) and stirred at room temperature. After the reaction is completed, the residue is filtered and the filtrate is concentrated, thereby obtaining 5-(fluoromethyl)-2-methyl-pyrazole-3-carboxylic acid. (Step 6) 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H obtained in Production Example 1 -To a solution of pyrrolo[2,3-d]pyrimidin-4-amine (5 mg) in THF (2 ml), DMF (0.02 ml), DIPEA (0.007 ml) and 5-(fluoromethyl)-2- were added Methyl-pyrazole-3-carboxylic acid (2.0 mg), and HATU (7 mg) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The obtained residue was purified by silica column chromatography to obtain the title compound.

[Example 30] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-4-( methanesulfonyl ) picolinamide (step 1) Combine methyl 4-chloropicolinic acid (343 mg), sodium methanesulfinate (204 mg), copper (I) chloride (19.8 mg), quinoline (26 mg), and NMP (3 ml) were stirred at 140°C for 5.5 hours under microwave irradiation. The reaction mixture was diluted with water and ethyl acetate, insoluble matter was separated by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography to obtain methyl 4-(methanesulfonyl)pyridinecarboxylate. (Step 2) Add 0.2 N aqueous sodium hydroxide solution (2.6 ml) to a THF solution (1.3 ml) of 4-(methanesulfonyl)pyridinecarboxylic acid methyl ester (113 mg), and stir at room temperature for 30 minutes. The reaction mixture was concentrated to obtain sodium 4-(methanesulfonyl)picolinate. (Step 3) Use 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-amine instead of 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl- used in Example 13 (step 3) 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, using sodium 4-(methanesulfonyl)pyridinecarboxylate instead of 5-methylpyridin-2-carboxylic acid Except for the acid, the same method as in Example 13 (step 3) was carried out, whereby the above-mentioned title compound was obtained.

[Example 31] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-4- methoxynicotinamide uses 4-methoxynicotinic acid instead of 5-(fluoromethyl)-2-methyl used in Example 29 Except for using pyrazole-3-carboxylic acid, the same method as in Example 29 (step 6) was carried out, thereby obtaining the above-mentioned title compound.

[Example 32] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-5-( dimethylamino ) pyridox - 2- carboxylic acid is used instead of 5-(dimethylamino)pyridox-2-carboxylic acid. Except for the 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17, the above-mentioned title compound was obtained by performing the same method as in Example 17.

[Example 33] N-(4-(4- amino- 6-( propyn -1- yl )-5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidine -7- yl ) bicyclo [2.2.1] heptan -1- yl )-1- methyl -1H- pyrazole -5- carboxamide (step 1) (4-( 4-Amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl) To a solution of tert-butyl carbamate (40 mg) in DMSO (2 ml), bis(triphenylphosphine)palladium(II) dichloride (10 mg), copper iodide (I) (6 mg), DIPEA (0.02 ml) and propyne DMF solution (1 M, 0.15 ml) were stirred at 80°C overnight under a nitrogen atmosphere. The reaction mixture was purified using reverse phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain (4-(4-amino-6-(propyn-1-yl)-5-(quinoline-3- tert-butyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate. (Step 2) Using (4-(4-amino-6-(propyn-1-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamic acid tert-butyl ester was used instead of (4-(4-amino) used in Production Example 1 (Step 8) -6-Ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamic acid Except for the third butyl ester, the same method as in Production Example 1 (step 8) was carried out to obtain 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-(propanyl) Alkyn-1-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. (Step 3) Use 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-(propyn-1-yl)-5-(quinoline-) obtained in the above step 2. 3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 1-methyl-1H-pyrazole-5-carboxylic acid were used in place of the 7-(4-amine used in Example 15 Bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 5- Except for chloropicopyrrolidone-2-carboxylic acid, the same method as in Example 15 was carried out, thereby obtaining the above-mentioned title compound.

[Example 34] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptan -1- yl )-5- cyanonicotinamide 7-(4-aminobicyclo[2.2.1]heptan-1-yl)- obtained in Production Example 1 To a solution of 6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg) in DMF (1 ml) was added DIPEA (0.004 ml) , 5-cyanopyridine-3-carboxylic acid (5 mg), and add WSC (4 mg) and HOBT (3 mg). After stirring at 50° C. for 2 hours, the reaction mixture was purified by reverse-phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the above-mentioned title compound.

[Example 35] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptan -1- yl )-5- fluoronicotinamide 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6 obtained in Production Example 1 To a solution of -ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg) in DMSO (1 ml), DIPEA (0.004 ml) was added. 5-fluoropyridine-3-carboxylic acid (5 mg), and add WSC (4 mg) and HOBT (3 mg). After stirring at 50° C. for 1 hour, the reaction mixture was purified by reverse-phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the above-mentioned title compound.

[Example 36] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-5- methyl -1,2,4- diadiazole -3- carboxamide uses 5-methyl-1,2,4-diadiazole-3 -Lithium carboxylate replaced 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17, except that the same method as in Example 17 was carried out to obtain The title compound above.

[Example 37] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-5- methylpyridine -2- carboxylic acid was used instead of 5-(fluoromethyl) used in Example 29. yl)-2-methyl-pyrazole-3-carboxylic acid, except that the same method as in Example 29 (step 6) was carried out, thereby obtaining the above-mentioned title compound.

[Example 38] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-6-( fluoromethoxy ) pyridine - 2- methamide (step 1) Add 6-bromopyridine-2-ol (221 mg), 4- A mixture of fluoromethyl toluenesulfonate (200 mg), cesium carbonate (383 mg), and DMPU (1.6 ml) was stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography to obtain 2-bromo-6-(fluoromethoxy)pyridine. (Step 2) Place a mixed solution of 2-bromo-6-(fluoromethoxy)pyridine (179 mg) in DMA (1.5 ml) and methanol (3 ml) into a pressure-resistant tube, and add sodium acetate ( 124 mg) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride dichloromethane adduct (28 mg), stirred at 50°C for 18 seconds in a carbon monoxide atmosphere hours. After the reaction mixture was cooled to room temperature, it was diluted with water and ethyl acetate, insoluble matter was separated by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography to obtain 6-(fluoromethoxy)pyridine-2-carboxylic acid methyl ester. (Step 3) Use 6-(fluoromethoxy)pyridine-2-carboxylic acid methyl ester instead of 4-(methanesulfonyl)pyridinecarboxylic acid methyl ester used in Example 30 (Step 2), except , carry out the same method as Example 30 (step 2), thereby obtaining sodium 6-(fluoromethoxy)pyridine-2-carboxylate. (Step 4) Use 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-amine instead of 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl- used in Example 13 (step 3) 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, using sodium 6-(fluoromethoxy)pyridin-2-carboxylate instead of 5-methyl Except for pyridine-2-carboxylic acid, the same method as in Example 13 (step 3) was carried out, thereby obtaining the above-mentioned title compound.

[Example 39] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) acetamide The above-mentioned title compound was obtained by performing the same method as in Example 1 except using acetic anhydride instead of benzyl chloride used in Example 1. .

[Example 40] 7-(4-(( dimethylamino ) methyl ) bicyclo [2.2.1] heptan -1- yl )-6- ethynyl- 5-( quinolin- 3- yl ) -7H- pyrrolo [2,3-d] pyrimidin -4- amine (step 1) (4-(4-amino-6-ethynyl-5-(quinoline-3) obtained in Example 10 -7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)methanol (30 mg), Dess-Martin periodane (47 mg ), dichloromethane (2.9 ml) was stirred at room temperature for 10 minutes. The reaction mixture was diluted with sodium thiosulfate aqueous solution and saturated sodium bicarbonate water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography to obtain 4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-carboxaldehyde. (Step 2) In 4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2. 1] To a methanol solution (0.5 ml) of heptane-1-carbaldehyde (5 mg) was added 2 M dimethylamine THF solution (0.012 ml). After the reaction mixture was stirred at room temperature for 30 minutes, 0.5 M sodium cyanoborohydride-0.25 M zinc chloride in methanol solution (0.07 ml) was added. After the reaction mixture was stirred at 40° C. for 30 minutes, the reaction mixture was purified by alkaline silica gel column chromatography and concentrated. The obtained residue was purified by reverse phase HPLC to obtain the above-mentioned title compound.

[Example 41] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) furan -2- carboxamide The same procedure as in Example 1 was carried out except that 2-furancarboxyl chloride was used instead of benzyl chloride used in Example 1. method, thereby obtaining the above-mentioned title compound.

[Example 42] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) imidazo [1,2-a] pyridino - 8- carboxamide Use imidazo[1,2-a]pyridox-8-carboxylic acid instead of Example 17 Except for using 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid, the same method as in Example 17 was carried out to obtain the title compound.

[Example 43] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) isonicotinamide 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl obtained in Production Example 1 To a solution of -5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (9 mg) in THF (0.5 ml), DIPEA (0.008 ml) and isonicotine were added acid (42 mg), and HATU (13 mg) was added. After stirring at room temperature for 30 minutes, dichloromethane (0.5 ml) was added, and the reaction mixture was concentrated after stirring overnight. The obtained residue was purified by reverse phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the title compound.

[Example 44] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) isoethazole -5- carboxamide, except that isoethazole-5-carboxamide chloride was used instead of benzyl chloride used in Example 1. The above-mentioned title compound was obtained in the same manner as in Example 1.

[Example 45] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) nicotinamide, except that nicotinic acid was used instead of isonicotinic acid used in Example 43, the same method as in Example 43 was performed, thereby obtaining the above Title compound.

[Example 46] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) ethazole -2- methamide Use ethazole-2-carboxylic acid instead of 1-(2-methoxyethyl)-1H- used in Example 17 Except for pyrazole-5-carboxylic acid, the same method as in Example 17 was carried out, thereby obtaining the above-mentioned title compound.

[Example 47] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) ethazole -5- methamide Use ethazole-5-carboxylic acid instead of 1-(2-methoxyethyl)-1H- used in Example 17 Except for pyrazole-5-carboxylic acid, the same method as in Example 17 was carried out, thereby obtaining the above-mentioned title compound.

[Example 48] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) pyridine - 2- carboxamide, except that 2-pyridinecarboxylic acid was used instead of pyrimidine-5-carboxylic acid used in Example 2. The same procedure as in Example 2 was carried out. 2, the above-mentioned title compound was obtained by the same method.

[Example 49] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptane -1- yl ) pyridine -3- carboxylic acid was used instead of 1-(2-methoxyethyl)-1H- used in Example 17 . Except for pyrazole-5-carboxylic acid, the same method as in Example 17 was carried out, thereby obtaining the above-mentioned title compound.

[Example 50] 1-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-3- ethyl urea The same method as in Example 1 was carried out except that ethyl isocyanate was used instead of benzyl chloride used in Example 1. This gives the above title compound.

[Example 51] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) pyrimidin -2- methamide to 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline Phin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10 mg), pyrimidine-2-carboxylic acid (2.5 mg), HATU (14.5 mg), DIPEA (0.013 ml) A mixed solution of THF (1 ml) and DMF (0.01 ml) was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography to obtain the above-mentioned title compound.

[Example 52] 1-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-3- ethylthiourea The same procedure as in Example 1 was carried out except that ethyl isothiocyanate was used instead of benzyl chloride used in Example 1. method, thereby obtaining the above-mentioned title compound.

[Example 53] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptan -1- yl ) thiazole -2- carboxamide 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6- obtained in Production Example 1 To a solution of ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg) in DMF (1 ml), DIPEA (0.004 ml) and thiazole were added -2-carboxylic acid (5 mg), and add WSC (4 mg) and HOBT (3 mg). After stirring at 50° C. for 1 hour, the reaction mixture was purified by reverse-phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the above-mentioned title compound.

[Example 54] 6- ethynyl -7-(4-(((2- fluoroethyl ) amino ) methyl ) bicyclo [2.2.1] heptan -1- yl )-5- ( quinoline- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -4- amine The 4-(4-amino-6-ethynyl-5-(quinoline) obtained in Example 40 (step 1) Phin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-carbaldehyde (7.7 mg), 2-fluoroethylamine hydrochloride (3.8 mg), DIPEA (0.0066 ml) in methanol (0.5 ml) and THF (0.5 ml) were stirred at room temperature for 30 minutes. 0.5 M sodium cyanoborohydride-0.25 M zinc chloride in methanol solution (0.1 ml) was added to the reaction mixture. After the reaction mixture was stirred at room temperature for 30 minutes, the reaction mixture was purified by alkaline silica gel column chromatography and concentrated. The obtained residue was purified by reverse phase HPLC to obtain the above-mentioned title compound.

[Example 55] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.2] octane -1- yl )-2-( dimethylamino ) acetamide 7-(4-aminobicyclo[2.2.2]octane-1 obtained in Production Example 2 To a solution of -yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg) in DMF (1 ml) was added DIPEA (0.004 ml), N,N-dimethylglycine (0.003 ml), and added WSC (4 mg) and HOBT (3 mg). After stirring at 60° C. for 2 hours, the reaction mixture was purified by reverse-phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the above-mentioned title compound.

[Example 56] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.2] octane -1- yl )-6- methyl -2,6- diazaspiro [3.3] heptane -2- thiocarboamide 7-(4 obtained in Production Example 2 -Aminobicyclo[2.2.2]octane-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( Add DIPEA (0.013 ml) and 1,1'-thiocarbonyldiimidazole (9 mg) to a solution of 10 mg) in DMF (1 ml), and stir at room temperature for 30 minutes. Furthermore, 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride (9 mg) was added, and the mixture was stirred at 60°C for 4 hours. The reaction mixture was purified by reverse phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the above title compound.

[Example 57] N-[4-(4- amino -6- ethynyl -5- quinolin -3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl )-1 - Bicyclo [2.2.1] heptan -1- yl ] -N,5- dimethylpyridine -2- methamide (step 1) N-(4-(4-) obtained in Example 37 Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)- A mixture of 5-methylpyridine-2-formamide (100 mg) and N,N-dimethylformamide dimethyl acetal (1 ml) was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature, diisopropyl ether (1 ml) was added, and stirred at room temperature for 1 hour. The obtained solid was filtered and washed with diisopropyl ether to obtain crude (E)-N-(4-(4-((dimethylamino)methylene)amino)-6- Ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyridine 𠯤-2-methamide. (Step 2) Crude (E)-N-(4-(4-((dimethylamino)methylene)amino)-6-ethynyl-5-( obtained in the above step 1 Quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyridin-2-methane Add methyl iodide (0.02 ml) and excess sodium hydride to a mixture of amine (10 mg) and THF (1 ml), and stir at room temperature for 15 minutes. DMF (0.2 ml) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated and purified by reverse phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the above title compound.

[Example 58] N-[4-(4- amino -6- ethynyl - 5- quinolin - 3- ylpyrrolo [2,3-d] pyrimidin -7- yl )-1- bicyclo [2.2 .1] Heptan -1- yl ]-N- methylethazole -2- carboxamide (step 1) using N-(4-(4-amino-6-ethynyl) obtained in Example 46 -5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)ethazole-2-methamide Instead of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7- used in Example 57 base) bicyclo[2.2.1]heptan-1-yl)-5-methylpyridine-2-carboxamide, except that the same method as in Example 57 (step 1) was carried out to obtain crude (E)-N-(4-(4-(((dimethylamino)methylene)amino)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)ethazole-2-methamide. (Step 2) Crude (E)-N-(4-(4-((dimethylamino)methylene)amino)-6-ethynyl-5-( obtained in the above step 1 Quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)ethazole-2-methamide (7 mg) , THF (2 ml), add methyl iodide (0.02 ml) and excess sodium hydride, stir at room temperature for 15 minutes, and stir at 50°C for 20 minutes. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was washed with water and saturated brine, dried, filtered and concentrated over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain (E)-N-(4-(4-((dimethylamino)methylene)amino)-6-ethynyl- 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-N-methylethazole-2 -Formamide. (Step 3) (E)-N-(4-(4-((dimethylamino)methylene)amino)-6-ethynyl-5-(quinoline) obtained in the above step 2 Phin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-N-methylethazole-2-methamide (7 mg) and 7 M ammonia-methanol solution (1 ml) were stirred at room temperature overnight and then stirred at 60°C for 4 hours. The reaction mixture was concentrated and purified by reverse phase preparative HPLC (water: acetonitrile (0.1% formic acid)) to obtain the above title compound.

[Example 59] (4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2 .1] To a solution of pyridin - 2- ylmethyl heptan-1-yl)carbamate in pyridin -2-ylmethanol (100 mg) in THF (1 ml) was added 1,1'-carbonyldiimidazole (147 mg) and stirred at room temperature for 2 hours. 7-(4-Aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H obtained in Production Example 1 was added to the reaction mixture. -pyrrolo[2,3-d]pyrimidin-4-amine (15 mg), stir at 40°C for 12 hours. The reaction mixture was concentrated, and the obtained residue was purified by reverse-phase HPLC to obtain the title compound.

[Example 60] 2-((4-(4- amino -6- ethynyl- 5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) Bicyclo [2.2.1] heptan -1- yl ) aminomethyl ) pyridine 1- oxide 7-(4-aminobicyclo[2.2.1]heptan-1-yl obtained in Production Example 1 )-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20 mg) in DMSO (1 ml) was added with DIPEA (0.013 ml), picolinic acid-N-oxide (7 mg), and added WSC (15 mg) and HOBT (12 mg). After stirring at room temperature for 22 hours, the reaction mixture was purified by reverse phase preparative HPLC to obtain the above title compound.

[Example 61] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] heptan -1- yl ) 7- ( 4- aminobicyclo [2.2.1]heptan-1 - yl)-6 obtained in Production Example 1 To a solution of -ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (7.5 mg) in THF (1 ml), DIPEA (0.03 ml), 4-(Chlorocarbonyl)piperidine-1-carboxylic acid tert-butyl ester (4.7 mg), stir at room temperature for 10 minutes. After the reaction mixture was concentrated, it was purified by reverse phase preparative HPLC to obtain the above title compound.

[Example 62] (S)-N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidine -7 -Bicyclo [2.2.1] heptan -1- yl ) 𠰌 line -2- carboxamide (step 1 ) 7- ( 4 - aminobicyclo[2.2.1]heptanyl) obtained in Production Example 1 Alk-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (60 mg) in DMSO (2 ml) Add DIPEA (0.04 ml), (S)-4-(tert-butoxycarbonyl)𠰌line-2-carboxylic acid (33 mg), and HATU (69 mg), and stir at room temperature for 30 minutes. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography to obtain (S)-2-((4-(4-amino-6-ethynyl-5-(quinolin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)aminomethanoyl)noline-4-carboxylic acid tert-butyl ester. (Step 2) (S)-2-((4-(4-amino-6-ethynyl-5-(quinolin-3-yl))-7H-pyrrolo[2] obtained in the above step 1 Chloroform (1 ml) was added to tert-butyl ,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)aminoformyl)𠰌line-4-carboxylate (87 mg) ), trifluoroacetic acid (0.5 ml), stir at room temperature for 30 minutes. The reaction mixture was concentrated and purified by alkaline silica gel column chromatography to obtain the title compound.

[Example 63] (S)-N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidine -7 - ( S ) -N-(4-(4-amine) bicyclo [2.2.1 ] heptan -1- yl )-4- methylnoline -2- methamide obtained in Example 63 Base-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-4 -To a mixture of -methyl 𠰌line-2-carboxamide (72 mg), THF (2 ml), and 37% formaldehyde aqueous solution (0.05 ml), 0.5 M sodium cyanoborohydride-0.25 M zinc chloride methanol solution ( 0.5 ml) and stir at room temperature for 15 minutes. Water was added to the reaction mixture, and extraction was performed with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by alkaline silica column chromatography to obtain the title compound.

[Example 64] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) imidazo [1,2-a] pyridine -3- carboxylic acid was used instead of imidazo[1,2-a]pyridine-3-carboxylic acid in Example 16 The above-mentioned title compound was obtained by carrying out the same method as Example 16 except using [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid.

[Example 65] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) imidazo [1,2-a] pyridino - 3- carboxamide Use imidazo[ 1,2-a ]pyridox-3-carboxylic acid instead of Example 13 The title compound was obtained by performing the same method as in Example 13 (Step 3) except that 1-methyl-1H-pyrazole-5-carboxylic acid was used in (Step 3).

[Example 66] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-5-( hydroxymethyl ) pyridine - 2- formamide (step 1) in methanol of methyl 5-formylpyridinecarboxylate (0.2 g) (1.0 ml), add molecular sieve 3A (0.1 g), methyl orthoformate (0.26 ml), and p-toluenesulfonic acid monohydrate (0.23 g), and stir at 70°C overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain methyl 5-(dimethoxymethyl)pyridoxalcarboxylate. (Step 2) In a mixed solvent of THF (1.2 ml) and methanol (1.2 ml) of methyl 5-(dimethoxymethyl)pyridoxalcarboxylate (0.26 g) obtained in the above step 1, add Add 0.5 M sodium hydroxide aqueous solution (2.4 ml) at 0°C and stir for 1 hour. The reaction mixture was concentrated, thereby obtaining sodium 5-(dimethoxymethyl)pyridoxcarboxylate. (Step 3) 7-(4-Aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H obtained in Production Example 1 -To a solution of pyrrolo[2,3-d]pyrimidin-4-amine (200 mg) in DMSO (5.1 ml), add DIPEA (0.26 ml) and 5-(dimethoxymethyl) obtained in step 2 above. ) Sodium pyridine carboxylate (0.11 g), HATU (0.29 g), stir at room temperature for 1 hour. Water (10 ml) was added to the reaction mixture, stirred at room temperature for 1 hour, and then the solid was filtered. The obtained solid was suspended in a mixed solvent of ethyl acetate (4 ml) and methanol (4 ml), and stirred at room temperature for 1 hour. The solid was filtered and washed with methanol to obtain N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] Pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-(dimethoxymethyl)pyridin-2-methamide. (Step 4) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] obtained in the above step 3) A solution of pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-(dimethoxymethyl)pyridin-2-methamide (0.33 g) in THF (3.3 ml) Trifluoroacetic acid (3.3 ml) and water (1.6 ml) were added, and the mixture was stirred at 60°C overnight. The reaction mixture was neutralized with an aqueous sodium hydroxide solution, and extracted with ethyl acetate-THF (1:1). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain crude N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)) -7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methanoylpyridin-2-methamide. (Step 5) Crude N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d) obtained in the above step 4 ]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methanoylpyridin-2-methamide (10 mg) in THF (1 ml), methanol (1 ml) Add sodium borohydride (1.4 mg) to the mixed solution and stir at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by reverse-phase preparative HPLC to obtain the title compound.

[Example 67] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-5-(( methylamino ) methyl ) pyridine - 2- methamide Crude N-(4) obtained in Example 66 (step 4) -(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1 -Add 2 M methylamine methanol solution (0.03 ml) to a mixed solution of -5-formylpyridine-2-formamide (10 mg) in THF (0.5 ml) and methanol (0.5 ml), and add Stir at room temperature for 30 minutes. 0.5 M sodium cyanoborohydride-0.25 M zinc chloride methanol solution (0.1 ml) was added to the reaction mixture, and stirred at room temperature for 1.5 hours. After adding 2 M methylamine methanol solution (0.03 ml) to the reaction mixture, 30 minutes later, 0.5 M sodium cyanoborohydride-0.25 M zinc chloride methanol solution (0.1 ml) was added, and stirred at room temperature for 1 hour. . After the reaction mixture was concentrated, it was purified by reverse phase preparative HPLC to obtain the title compound.

[Example 68] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) -5 -(( dimethylamino ) methyl ) pyridine -2- methamide Use dimethylamine hydrochloride instead of that used in Example 67 2 M methylamine methanol solution, and further adding DIPEA (0.06 ml), the same method as in Example 67 was carried out, thereby obtaining the above title compound.

[Example 69] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl ) -5-( 𠰌 linylmethyl ) pyridine -2- methamide Use 𠰌line instead of the 2 M methylamine methanol solution used in Example 67, except Except for this, the same method as in Example 67 was carried out, whereby the above-mentioned title compound was obtained.

[Example 70] N-(4-(4- amino -6- ethynyl -5-( quinolin- 3- yl )-7H- pyrrolo [2,3-d] pyrimidin -7- yl ) bicyclo [2.2.1] Heptan -1- yl )-5-( dimethylphosphate ) picolinamide (step 1) in 1,4-dimethyl 6-bromonicotinic acid methyl ester (0.05 g) Tripotassium phosphate (0.15 g), dimethylphosphine oxide (0.036 ml), and 1,3-bis(diphenylphosphine)propane nickel(II) chloride (0.013 g) were added to the hexane (1 ml) solution. Stir at 120°C for 12 hours under nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by silica column chromatography to obtain methyl 5-(dimethylphosphate)picolinate. (Step 2) Add 1 N aqueous sodium hydroxide solution to the THF (0.5 ml) and methanol (0.5 ml) solution of 5-(dimethylphosphate)picolinate methyl ester (0.019 g) obtained in the above step 1. (0.5 ml) and stir at room temperature for 2 hours. 1 N hydrochloric acid (0.5 ml) was added to the reaction mixture and concentrated to obtain crude 5-(dimethylphosphono)picolinic acid. (Step 3) Use the crude 5-(dimethylphosphono)picolinic acid obtained in the above Step 2 instead of the 1-methyl-1H-pyrazole-5-carboxylic acid used in Example 13 (Step 3) , Except for this, the same method as in Example 13 (step 3) was carried out to obtain the above-mentioned title compound.

The chemical structural formulas and physical property values of the compounds of Examples 1 to 70 are shown in Table 1 below. [Table 1]

Comparative Example A (R)-1-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1 -yl)prop-2-en-1-one [Chemical 11]

Comparative Example B (R)-1-(3-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl )pyrrolidin-1-yl)prop-2-en-1-one [Chemical 12] It was synthesized according to the method described in the specification of International Publication No. WO2013/118817.

Test Examples The following test methods were used to evaluate the compounds of the above examples and comparative examples. Test Example 1 Various EGFR kinase activity inhibitory effects test ( in vitro ) 1) EGFR (d746-750/T790M/C797S) kinase inhibitory activity assay To measure the effects of the compounds of the above examples and comparative examples on EGFR (d746-750/T790M/C797S) Inhibitory activity of kinase activity. In this inhibitory activity measurement material, the following kinase proteins were used, which were expressed in insect cells Sf9 by the baculovirus expression system and human fused to the amino terminus with a glutathione-S-transferase (GST) tag. The cytoplasmic region of EGFR (d746-750/T790M/C797S) was purified using a glutathione sepharose gel column (Serial Number 1). Using PerkinElmer's LabChip (registered trademark) series reagent FL-Peptide 22 as the substrate peptide as a reference, a peptide in which the N-terminus was biotinylated (biotin-EEPLYWSFPAKKK) was synthesized.

The inhibitory activity assay method is as follows. First, the compounds of the present invention are dissolved in dimethylsulfoxide (DMSO), and then serial dilutions are prepared using DMSO. Next, mix the substrate peptide in a serial dilution solution of the compound (the final concentration of DMSO in the kinase reaction is 2.5%) or DMSO (the final concentration is 2.5%), and the kinase reaction buffer (Carna Biosciences Co., Ltd.) (final concentration: 250 nM), magnesium chloride (final concentration: 10 mM), manganese chloride (final concentration: 10 mM), ATP (final concentration: 6 μM), and then add EGFR (d746-750/T790M/C797S ) protein and incubate at 25°C for 120 minutes to perform a kinase reaction. EDTA was added to the final concentration of 24 mM to terminate the reaction, and a phosphotyrosine detection solution containing europium-labeled anti-phosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA (PerkinElmer) was added. , let stand at room temperature for more than 2 hours. As a base, DMSO was used instead of the DMSO solution of the compound. EDTA was added before adding the EGFR (d746-750/T790M/C797S) protein and incubated at 25°C for 120 minutes. Also add the detection solution and let it stand for more than 2 hours. Finally, the fluorescence amount of all the test samples was measured at two wavelengths of 620 nm and 665 nm using PHERAstar FS (BMG LABTECH) when irradiated with excitation light of 337 nm wavelength, and the ratio of the fluorescence amount of the two wavelengths was obtained as data. .

In the analysis of the measurement data, first, the fluorescence amount ratio data in the sample in which the kinase reaction was performed by adding DMSO at a final concentration of 2.5% was set to the phosphorylation reaction inhibition rate of 0%, and the fluorescence amount ratio data in the substrate was set to phosphorylation. The reaction inhibition rate is 100%, and the concentration of the compound that inhibits 50% of the phosphorylation reaction caused by EGFR (d746-750/T790M/C797S) is defined as the IC50 value (nM).

Moreover, as control compounds, the following Comparative Example A (Example 3 in WO2013/118817) and Comparative Example B (Example 35 in WO2013/118817), which are known to have EGFR inhibitory activity, were used.

The measurement data are shown in Table 2. [Table 2] Table 2 EGFR (d746-750/T790M/C797S) IC50 value (nM) EGFR (d746-750/T790M/C797S) IC50 value (nM) Example 1 <0.3 Example 31 <0.3 Example 2 <0.3 Example 32 <0.3 Example 3 <0.3 Example 33 <0.3 Example 4 0.36 Example 34 <0.3 Example 5 0.32 Example 35 <0.3 Example 6 <0.3 Example 36 <0.3 Example 7 0.80 Example 37 <0.3 Example 8 <0.3 Example 38 <0.3 Example 9 <0.3 Example 39 <0.3 Example 10 <0.3 Example 40 <0.3 Example 11 <0.3 Example 41 <0.3 Example 12 <0.3 Example 42 <0.3 Example 13 <0.3 Example 43 <0.3 Example 14 <0.3 Example 44 <0.3 Example 15 <0.3 Example 45 <0.3 Example 16 <0.3 Example 46 <0.3 Example 17 <0.3 Example 47 <0.3 Example 18 <0.3 Example 48 <0.3 Example 19 <0.3 Example 49 <0.3 Example 20 <0.3 Example 50 <0.3 Example 21 <0.3 Example 51 <0.3 Example 22 <0.3 Example 52 <0.3 Example 23 <0.3 Example 53 <0.3 Example 24 <0.3 Example 54 <0.3 Example 25 <0.3 Example 55 <0.3 Example 26 <0.3 Example 56 <0.3 Example 27 <0.3 Example 57 <0.3 Example 28 <0.3 Example 58 <0.3 Example 29 <0.3 Comparative example A 142 Example 30 <0.3 Comparative example B 26

2) EGFR (L858R/T790M/C797S) kinase inhibitory activity assay The inhibitory activity of the compounds of the present invention on EGFR (L858R/T790M/C797S) kinase activity was determined.

The materials, measurement methods, and data analysis methods used are roughly the same as those shown in the EGFR (d746-750/T790M/C797S) kinase inhibitory activity measurement section. However, the kinase protein in the material uses the following substance, which is expressed in the cytoplasmic region of human EGFR (L858R/T790M/C797S) fused to the amino terminus of the GST tag in insect cells Sf9 through the baculovirus expression system, Purified using a glutathione agarose gel column (Serial Number 2). In the assay method, the final concentration of ATP was set to 0.5 μM. Finally, the IC50 value (nM) of each compound against EGFR (L858R/T790M/C797S) was determined through data analysis.

Moreover, as control compounds, the following Comparative Example A (Example 3 in WO2013/118817) and Comparative Example B (Example 35 in WO2013/118817), which are known to have EGFR inhibitory activity, were used.

The measurement data are shown in Table 3. [table 3] table 3 EGFR (L858R/T790M/C797S) IC50 value (nM) EGFR (L858R/T790M/C797S) IC50 value (nM) Example 1 0.46 Example 31 0.52 Example 2 <0.3 Example 34 <0.3 Example 3 <0.3 Example 35 0.50 Example 4 0.38 Example 36 0.56 Example 6 0.70 Example 37 0.52 Example 10 0.56 Example 38 0.66 Example 11 0.69 Example 39 0.36 Example 12 0.39 Example 41 0.39 Example 15 0.52 Example 42 <0.3 Example 16 0.36 Example 44 0.32 Example 17 0.79 Example 46 0.41 Example 18 0.42 Example 47 0.59 Example 19 <0.3 Example 48 <0.3 Example 20 0.44 Example 49 0.47 Example 22 0.42 Example 50 0.68 Example 23 0.42 Example 51 0.34 Example 24 <0.3 Example 52 0.60 Example 25 0.60 Example 53 0.69 Example 26 0.62 Example 58 1.5 Example 27 0.47 Comparative example A 102 Example 28 1.1 Comparative example B 43 Example 29 0.31 Example 30 0.33

3) EGFR (d746-750/C797S) kinase inhibitory activity assay The inhibitory activity of the compounds of the present invention on EGFR (d746-750/C797S) kinase activity was determined.

The materials, measurement methods, and data analysis methods used are generally the same as those shown in the EGFR (d746-750/T790M/C797S) kinase inhibitory activity measurement section. However, the kinase protein in the material uses purified recombinant human EGFR (d746-750/C797S) protein purchased from SignalChem, and the kinase reaction buffer uses 13.5 mM Tris (pH7.5) and 2 mM dithiothreitol. , 0.009% Tween-20, in the assay method, set the final concentration of ATP to 14 μM, set the final concentration of magnesium chloride to 20 mM, set the final concentration of manganese chloride to 12.5 mM, and set the culture setting of the kinase reaction for 60 minutes and set the final concentration of EDTA used to terminate the kinase reaction to 40 mM. Finally, the IC50 value (nM) of each compound for EGFR (d746-750/C797S) was determined through data analysis.

Moreover, as control compounds, the following Comparative Example A (Example 3 in WO2013/118817) and Comparative Example B (Example 35 in WO2013/118817), which are known to have EGFR inhibitory activity, were used.

The measurement data are shown in Table 4. [Table 4] Table 4 EGFR (d746-750/C797S) IC50 value (nM) EGFR (d746-750/C797S) IC50 value (nM) Example 1 1.8 Example 31 0.49 Example 2 0.29 Example 32 0.59 Example 3 <0.3 Example 33 1.9 Example 4 1.0 Example 34 0.46 Example 5 1.2 Example 35 0.55 Example 6 2.1 Example 36 0.61 Example 7 2.3 Example 37 0.50 Example 8 0.73 Example 38 0.56 Example 9 0.36 Example 39 0.75 Example 10 0.62 Example 40 2.6 Example 11 1.6 Example 41 1.4 Example 12 2.4 Example 42 0.48 Example 13 0.67 Example 43 0.73 Example 14 0.79 Example 44 0.73 Example 15 0.79 Example 45 0.67 Example 16 0.45 Example 46 0.43 Example 17 0.61 Example 47 0.33 Example 18 0.78 Example 48 0.46 Example 19 <0.3 Example 49 0.49 Example 20 0.68 Example 50 0.97 Example 21 0.78 Example 51 0.83 Example 22 <0.3 Example 52 1.5 Example 23 0.70 Example 53 0.88 Example 24 0.50 Example 54 1.5 Example 25 0.40 Example 55 0.86 Example 26 0.71 Example 56 0.84 Example 27 1.2 Example 57 2.5 Example 28 0.89 Example 58 2.2 Example 29 0.32 Comparative example A 264 Example 30 0.64 Comparative example B 93

4) EGFR (L858R/C797S) kinase inhibitory activity assay The inhibitory activity of the compounds of the present invention on EGFR (L858R/C797S) kinase activity was determined.

The materials, measurement methods, and data analysis methods used are generally the same as those shown in the EGFR (d746-750/C797S) kinase inhibitory activity measurement section. However, the kinase protein in the material was purified recombinant human EGFR (C797S/L858R) protein purchased from SignalChem. In the measurement method, the final concentration of ATP was set to 4 μM, and the incubation of the kinase reaction was set to 90 minutes. Finally, the IC50 value (nM) of each compound for EGFR (L858R/C797S) was determined through data analysis.

Moreover, as control compounds, the following Comparative Example A (Example 3 in WO2013/118817) and Comparative Example B (Example 35 in WO2013/118817), which are known to have EGFR inhibitory activity, were used.

The measurement data are shown in Table 5. [table 5] table 5 EGFR (L858R/C797S) IC50 value (nM) EGFR (L858R/C797S) IC50 value (nM) Example 1 2.8 Example 31 0.62 Example 2 0.46 Example 32 0.78 Example 3 0.37 Example 33 2.3 Example 4 1.5 Example 34 0.45 Example 5 2.8 Example 35 0.84 Example 6 4.6 Example 36 0.99 Example 7 2.9 Example 37 0.69 Example 8 1.4 Example 38 0.97 Example 9 1.0 Example 39 1.4 Example 10 0.95 Example 40 4.0 Example 11 2.4 Example 41 1.9 Example 12 3.8 Example 42 0.43 Example 13 0.69 Example 43 0.49 Example 14 1.3 Example 44 0.94 Example 15 1.0 Example 45 0.53 Example 16 0.49 Example 46 0.43 Example 17 0.66 Example 47 0.36 Example 18 0.67 Example 48 0.60 Example 19 0.30 Example 49 0.63 Example 20 1.2 Example 50 2.0 Example 21 0.98 Example 51 0.99 Example 22 0.35 Example 52 2.6 Example 23 0.84 Example 53 1.2 Example 24 0.59 Example 54 2.8 Example 25 0.59 Example 55 1.2 Example 26 0.84 Example 56 0.90 Example 27 2.4 Example 57 4.4 Example 28 1.7 Example 58 3.4 Example 29 0.39 Comparative example A 187 Example 30 1.2 Comparative example B 97

5)EGFR(WT) The inhibitory activity of the compounds of the present invention on EGFR (WT) kinase activity was determined.

The materials, measurement methods, and data analysis methods used are generally the same as those shown in the EGFR (d746-750/T790M/C797S) kinase inhibitory activity measurement section. However, as the kinase protein in the material, purified recombinant human EGFR (WT) purchased from Carna Biosciences was used, and in the measurement method, the final concentration of ATP was set to 1.5 μM. Finally, the IC50 value (nM) of each compound against EGFR (WT) was determined through data analysis.

Moreover, as control compounds, the following Comparative Example A (Example 3 in WO2013/118817) and Comparative Example B (Example 35 in WO2013/118817), which are known to have EGFR inhibitory activity, were used.

The measurement data are shown in Table 6. [Table 6] Table 6 EGFR (WT) IC50 value (nM) EGFR (WT) IC50 value (nM) Example 1 2.1 Example 31 1.5 Example 2 0.52 Example 32 1.0 Example 3 0.45 Example 33 1.9 Example 4 2.9 Example 34 0.84 Example 5 4.0 Example 35 1.3 Example 6 5.2 Example 36 2.6 Example 7 2.5 Example 37 0.92 Example 8 3.2 Example 38 1.6 Example 9 2.6 Example 39 1.5 Example 10 1.1 Example 40 5.0 Example 11 11 Example 41 2.1 Example 12 2.1 Example 42 0.31 Example 13 0.61 Example 43 1.7 Example 14 1.7 Example 44 0.80 Example 15 1.5 Example 45 1.9 Example 16 0.53 Example 46 0.79 Example 17 2.6 Example 47 0.41 Example 18 1.4 Example 48 0.75 Example 19 0.39 Example 49 0.86 Example 20 2.1 Example 50 1.2 Example 21 1.7 Example 51 0.94 Example 22 0.55 Example 52 0.88 Example 23 1.4 Example 53 1.9 Example 24 0.73 Example 54 6.3 Example 25 0.51 Example 55 1.2 Example 26 2.1 Example 56 0.94 Example 27 2.4 Example 57 5.9 Example 28 3.2 Example 58 3.9 Example 29 0.62 Comparative example A 1.6 Example 30 1.9 Comparative example B 0.95

Based on the results of Test Example 1-1) to 5), it was confirmed that the compound of the present invention is not only effective on EGFR (d746-750/C797S) and EGFR (L858R/C797S), but also on EGFR (d746-750/T790M/C797S) and EGFR (L858R/T790M/C797S) has stronger inhibitory activity than known compounds. In addition, from comparison with Comparative Examples A and B, it can be seen that the alkyne at the 6-position and the bicyclic ring structure at the 7-position have a significant impact on the inhibitory activity. This difference in activity caused by substituents was completely unknown and was a surprising discovery.

Test Example 2 Proliferation inhibitory activity test on wild-type and mutant EGFR -expressing cell lines ( in vitro ) (1) Mouse cell line Ba/F3- that stably expresses EGFR (d746-750/T790M/C797S) by gene introduction EGFR (d746-750/T790M/C797S), the mouse cell line Ba/F3-EGFR (L858R/T790M/C797S), which is genetically introduced and stably expresses EGFR (L858R/T790M/C797S), and the gene is introduced and stably expresses wild-type EGFR. The mouse cell line Ba/F3-EGFR (WT) was suspended in RPMI-1640 cell culture medium (RPMI-1640, 10% FBS, 100 units/ml of penicillin, and 0.1 mg/ml of streptomycin). The mouse cell line Ba/F3-EGFR (WT) was suspended using a medium containing EGF at a final concentration of 50 ng/ml in RPMI-1640 cell culture medium. Furthermore, the mouse cell line Ba/F3-EGFR (d746-750/T790M/C797S), which is genetically introduced and stably expresses EGFR (d746-750/T790M/C797S), and the mouse cell line Ba/F3-EGFR (d746-750/T790M/C797S), which is genetically introduced and stably expresses EGFR (L858R/T790M/C797S) ), the mouse cell line Ba/F3-EGFR (L858R/T790M/C797S), and the mouse cell line Ba/F3-EGFR (WT) that is genetically introduced and stably expresses wild-type EGFR are based on Test Example 1 in WO2018/079310 , produced using the nucleotide sequences encoding the proteins of SEQ ID NO: 1 and SEQ ID NO: 2. The cell suspension was seeded into each well of a 96-well flat bottom plate. The compound of the present invention was dissolved in DMSO, and DMSO was used to prepare a serial dilution of the test compound (1000 times the final concentration). The DMSO solution of the test compound or DMSO was diluted with the RPMI-1640 cell culture medium of each cell, and added to each well of the cell culture plate so that the final concentration of DMSO became 0.1%, and cultured in a medium containing 5% carbon dioxide. Incubate at 37°C for 3 days. The cell number before adding the test compound DMSO solution and after adding the culture was measured using CellTiter-Glo (registered trademark) (Promega Company) based on the protocol recommended by Promega Company.

In each cell, the cell growth inhibition rate of the wells in which the test compound was added at various concentrations was calculated according to the following formula. Then, for each test compound, the inhibition rate at each concentration was plotted, and the curve fitting software XLfit (IDBS Company) was used to calculate the concentration IC50 (nM) of the test compound at which the cell survival rate reached 50%. Cell survival rate (%)=T/C×100 T: Luminous intensity of the well after adding test compound solution and incubating for 3 days C: Luminous intensity of the well after adding DMSO and culturing for 3 days

Moreover, as control compounds, the following Comparative Example A (Example 3 in WO2013/118817) and Comparative Example B (Example 35 in WO2013/118817), which are known to have EGFR inhibitory activity, were used.

The results are shown in Table 7. [Table 7] Table 7 BaF3_EGFR (d746-750/T790M/C797S) IC50 value (nM) BaF3_EGFR (L858R/T790M/C797S) IC50 value (nM) BaF3_EGFR (WT) IC50 value (nM) Example 2 20 185 2646 Example 3 56 529 3330 Example 13 239 910 3596 Example 14 204 952 3500 Example 24 34 403 3790 Example 37 twenty one 270 2972 Example 43 57 417 3287 Example 45 42 305 3397 Example 46 19 204 2412 Example 48 twenty four 223 2487 Example 49 19 290 3072 Comparative example A 3658 2258 2462 Comparative example B 1075 3586 1046

The compound of the present invention shows weak proliferation inhibitory effect on wild-type EGFR expressing cell lines. In contrast, it was shown that it has a strong growth-inhibitory effect on EGFR (d746-750/T790M/C797S)-expressing cell lines and EGFR (L858R/T790M/C797S)-expressing cell lines. From this result, it was found that the compound of the present invention selectively exhibits a growth-inhibitory effect on cell lines expressing mutant EGFR.

Test Example 3 Various EGFR kinase activity inhibitory effects test ( in vitro ) 1) EGFR (d746-750/T790M/C797S) kinase inhibitory activity measurement In the same procedure as Test Example 1-1), the compounds of the above examples were measured on EGFR (d746-750/T790M/C797S) kinase activity inhibitory activity. The measurement data are shown in Table 8. [Table 8] Table 8 EGFR (d746-750/T790M/C797S) IC50 value (nM) Example 59 0.37 Example 60 <0.3 Example 61 <0.3 Example 62 <0.3 Example 63 <0.3 Example 64 <0.3 Example 65 <0.3 Example 66 <0.3 Example 67 <0.3 Example 68 <0.3 Example 69 <0.3 Example 70 <0.3

2) EGFR (L858R/T790M/C797S) kinase inhibitory activity measurement The inhibitory activity of the compound of the present invention on the EGFR (L858R/T790M/C797S) kinase activity was measured in the same procedure as Test Example 1-2). The measurement data are shown in Table 9. [Table 9] Table 9 EGFR (L858R/T790M/C797S) IC50 value (nM) Example 59 0.47 Example 60 <0.3 Example 61 1.6 Example 62 <0.3 Example 63 <0.3 Example 64 <0.3 Example 65 <0.3 Example 66 <0.3 Example 67 <0.3 Example 68 <0.3 Example 69 <0.3 Example 70 <0.3

3) EGFR (d746-750/C797S) kinase inhibitory activity measurement The inhibitory activity of the compound of the present invention on the EGFR (d746-750/C797S) kinase activity was measured in the same procedure as Test Example 1-3). The measurement data are shown in Table 10. [Table 10] Table 10 EGFR (d746-750/C797S) IC50 value (nM) Example 59 0.83 Example 60 0.30 Example 61 0.54 Example 62 0.34 Example 63 0.51 Example 64 0.86 Example 65 0.40 Example 66 <0.3 Example 67 0.30 Example 68 <0.3 Example 69 <0.3 Example 70 0.70

4) EGFR (L858R/C797S) kinase inhibitory activity measurement The inhibitory activity of the compound of the present invention on the EGFR (L858R/C797S) kinase activity was measured in the same procedure as Test Example 1, 4). The measurement data are shown in Table 11. [Table 11] Table 11 EGFR (L858R/C797S) IC50 value (nM) Example 59 1.7 Example 60 0.48 Example 61 1.1 Example 64 0.32 Example 65 <0.3 Example 66 <0.3 Example 67 0.37 Example 68 0.36 Example 69 0.59 Example 70 1.6

5) EGFR (WT) In the same procedure as Test Example 1, 5), the inhibitory activity of the compound of the present invention on the kinase activity of EGFR (WT) was measured. The measurement data are shown in Table 12. [Table 12] Table 12 EGFR (WT) IC50 value (nM) Example 59 2.2 Example 60 0.72 Example 61 2.7 Example 62 1.6 Example 63 2.8 Example 64 0.41 Example 65 <0.3 Example 66 <0.3 Example 67 0.35 Example 68 0.43 Example 69 0.74 Example 70 0.94

Based on the results of Test Example 2-1) to 5), it was confirmed that the compound of the present invention is not only effective on EGFR (d746-750/C797S) and EGFR (L858R/C797S), but also on EGFR (d746-750/T790M/C797S) and EGFR (L858R/T790M/C797S) has strong inhibitory activity.

Test Example 4 : Proliferation inhibitory activity test ( in vitro ) on wild-type and variant EGFR- expressing cell lines . In the same procedure as Test Example 2, the proliferation-inhibitory activity of the compound of the present invention on wild-type and variant EGFR-expressing cell lines was carried out. Experiment. The measurement data are shown in Table 13. [Table 13] Table 13 BaF3_EGFR (d746-750/T790M/C797S) IC50 value (nM) BaF3_EGFR (L858R/T790M/C797S) IC50 value (nM) BaF3_EGFR (WT) IC50 value (nM) Example 1 98 887 3485 Example 9 59 592 ＞2000 Example 16 32 283 1922 Example 18 124 1268 2475 Example 20 31 245 2652 Example 23 31 649 3189 Example 27 110 754 ＞2000 Example 35 44 348 2957 Example 36 59 448 ＞2000 Example 39 98 658 2362 Example 41 102 843 3244 Example 44 30 268 2264 Example 47 33 382 2064 Example 53 162 978 3289 Example 63 73 672 2994

The compound of the present invention shows weak proliferation inhibitory effect on wild-type EGFR expressing cell lines. In contrast, it was shown that it has a strong growth-inhibitory effect on EGFR (d746-750/T790M/C797S)-expressing cell lines and EGFR (L858R/T790M/C797S)-expressing cell lines. From this result, it was found that the compound of the present invention selectively exhibits a growth-inhibitory effect on cell lines expressing mutant EGFR.

Sequence: EGFR d746-750/T790M/C797S EGFR L858R/T790M/C797S [Sequence listing non-key text]

Sequence Numbers 1 and 2: Synthetic Protein

Claims (14)

A compound or a pharmaceutically acceptable salt thereof, represented by the following general formula (I):

[In the formula, R ¹ is a hydrogen atom or a C1-C3 alkyl group that may have a substituent, and X is NR ² R ³ or OR ⁴ or a monocyclic or polycyclic saturated or unsaturated heterocyclic group that may have a substituent Ring group, the above saturated or unsaturated heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazyl

base, hexamethyleneimine group,

Phylyl, thio

Phenyl, homopiper

base, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, 2,6-diazaspiro[3.3]heptane, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl ,

Azolyl, iso

azolyl,

Diazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridyl

base, da

base, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, pyrrolopyridyl, imidazopyridyl, imidazopyridyl

base, pyrazolopyridyl, triazolopyridyl, pyrrolopyrimidinyl, imidazopyrimidinyl, pyrazopyrimidinyl, benzofuranyl, benzo

Azolyl, benzothienyl, benzothiazolyl, benzofuryl, quinolyl, isoquinolyl, quinazolinyl, quinolyl

Phyllinyl, indolinyl, methylenedioxyphenyl, ethyldioxyphenyl, dihydrobenzofuranyl, R ² is a hydrogen atom, or a C1-C6 alkyl group that may have a substituent , R ³ is a hydrogen atom, C(=O)R ⁵ , C(=S)R ⁶ , a C1-C6 alkyl group which may have a substituent, or a C3-C7 cycloalkyl group which may have a substituent, and R ⁴ is Hydrogen atom, C1-C6 alkyl group which may have a substituent, C3-C7 cycloalkyl group which may have a substituent, carbonylamino group which may have a substituent, R ⁵ is a C1-C6 alkyl group which may have a substituent, which may C3-C7 cycloalkyl group with substituent, C1-C6 alkoxy group which may have substituent, amino group which may have substituent, monocyclic or polycyclic saturated heterocyclic group with 4-10 members which may have substituent Ring group, a 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group that may have a substituent, a 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group that may have a substituent, R ⁶ is A hydrogen atom, a C1-C6 alkyl group that may have a substituent, a C1-C6 mono- or dialkylamino group that may have a substituent, a C3-C7 cycloalkyl group that may have a substituent, or a substituent that may have 1 ~4 monocyclic or polycyclic saturated heterocyclic groups with 4 to 10 members selected from heteroatoms in nitrogen atoms, oxygen atoms and sulfur atoms, ring A is bicyclo[2.2.1]heptane or bicyclo[2.2 .2] Octane, the above substituent is selected from the following groups: halogen atom, cyano group, nitro group, amino group, hydroxyl group, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, second butyl, third butyl, pentyl, hexyl alkyl, selected from monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl , 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl haloalkyl, selected from cyclopropyl, cyclopropyl Cycloalkyl groups of butyl, cyclopentyl, cyclohexyl and cycloheptyl, aralkyl groups selected from benzyl, phenethyl, naphthylmethyl and naphthylethyl, methoxy and ethoxy groups , n-propoxy, isopropoxy, tert-butoxy alkoxy, methanesulfonyl, C1-C6 alkoxy-C1-C6 alkyl, selected from hydroxymethyl, hydroxyethyl, hydroxyl n-propyl, hydroxyisopropyl, hydroxyn-butyl, hydroxyisobutyl, hydroxysecond-butyl, hydroxytert-butyl, hydroxypentyl, hydroxyhexyl, hydroxyalkyl, fluoromethoxy, single C1- C6 alkylamino or di-C1-C6 alkylamino, mono-C1-C6 alkylamino-C1-C6 alkyl or di-C1-C6 alkylamino-C1-C6 alkyl, carbonyl amine, side Oxygen group, oxygen group, carboxyl group, alkoxycarbonyl group selected from methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, phosphine oxide group, the above saturated Or unsaturated heterocyclic group, selected from pyridylmethyl, pyrrolidinylmethyl,

Heterocycloalkyl groups of phyllylmethyl groups, and aromatic hydrocarbon groups selected from phenyl, naphthyl, and tetrahydronaphthyl groups, n represents any integer from 0 to 3]. For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or a C1-C3 alkyl group. For example, the compound of claim ¹ or ² or a pharmaceutically acceptable salt thereof ^, wherein ~7-membered monocyclic saturated or unsaturated heterocyclic group, R ² is a hydrogen atom or C1-C6 alkyl group, R ³ is C(=O)R ⁵ , C(=S)R ⁶ or may have a substituent C1-C6 alkyl group, the substituent is a cyano group, a halogen atom, or a monocyclic unsaturated heterocyclic ring with 5 to 7 members with 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. group, R ⁴ is a hydrogen atom, R ⁵ is a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 mono or dialkylamino group which may have a substituent, or a 5-10 member group which may have a substituent. Monocyclic or polycyclic unsaturated heterocyclic group, or 6-10 membered monocyclic or polycyclic aromatic hydrocarbon group, R ⁶ is a C1-C6 mono or dialkylamino group, or may have C1-C6 Alkyl group and a monocyclic or polycyclic saturated heterocyclic group with 1 to 4 members selected from nitrogen atoms, oxygen atoms and heteroatoms in sulfur atoms and 4 to 10 members. The definition of the above substituents is the same as claim 1 . For example, the compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein n is 0 or 1. For example, the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom. For example, the compound of claim ¹ or ² or a pharmaceutically acceptable salt thereof, wherein A monocyclic saturated or unsaturated heterocyclic group, R ² is a hydrogen atom, R ³ is C(=O)R ⁵ , R ⁵ is an optionally substituted C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 mono- or dialkylamino group, 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group which may have substituents, or 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group , the definition of the above substituents is the same as claim 1. For example, the compound of claim ¹ or ² or a pharmaceutically acceptable salt thereof, wherein A monocyclic saturated heterocyclic group, R ² is a hydrogen atom, R ³ is C(=O)R ⁵ , R ⁵ is a C1-C6 alkyl group that may have a halogen atom, or it may have a C1-C6 alkyl group and has 1 to 4 monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic groups with 5 to 10 members selected from heteroatoms in nitrogen atoms, oxygen atoms and sulfur atoms. For example, the compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein ring A is bicyclic [2.2.1] Heptane. For example, the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein n is 0. A compound or a pharmaceutically acceptable salt thereof, which is selected from the following compound groups: (1) 6-ethynyl-7-(4-

Phinylbicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(2)N-(4 -(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1 -yl)-1-methyl-1H-pyrazole-5-carboxamide (3)N-(4-(4-amino-6-ethynyl)-5-(quinolin-3-yl)-7H -pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-2,2-difluoroacetamide(4)N-(4-(4- Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)- 5-methyl-1,2,4-

Diazole-3-carboxamide(5)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine -7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyra

-2-Formamide(6)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7 -base)bicyclo[2.2.1]heptan-1-yl)

Azole-2-carboxamide(7)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)bicyclo[2.2.1]heptan-1-yl)pyridine

-2-Formamide(8)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)bicyclo[2.2.1]heptan-1-yl)na

-3-Formamide(9)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7 -Bicyclo[2.2.1]heptan-1-yl)pyrimidine-5-methamide(10)N-(4-(4-amino-6-ethynyl-5-(quinoline-3-) base)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-cyclopropyl-1H-pyrazole-5-methamide (11)N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2 .1]heptan-1-yl)iso

Azole-5-methamide. An anti-tumor agent comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition containing a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. For example, the compound of any one of claims 1, 2, and 10 or its pharmaceutically acceptable salt is used to treat tumors. The use of a compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, for producing an anti-tumor agent.